Advances in Urological Diagnosis and Imaging - AUDI (Vol. 3 - n. 1 - 2020) by Edizioni Scripta Manent

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ADVANCES IN UROLOGICAL DIAGNOSIS AND IMAGING EDITOR IN CHIEF Andrea B. Galosi CO-EDITOR Pasquale Martino

OFFICIAL JOURNAL of

S.I.E.U.N. Italian Society of Integrated Diagnostic in Urology, Andrology, Nephrology

Vol. 3 - n. 1 - 2020

ADVANCES

UROLOGICAL DIAGNOSIS AND IMAGING

Official Journal of S.I.E.U.N. EDITOR in CHIEF Andrea B. Galosi, Ancona (IT)

CO-EDITOR Pasquale Martino, Bari (IT)

ASSISTANT EDITOR Lucio Dell’Atti, Ancona (IT)

EDITORIAL BOARD Urology Ahmed Hashim, London (GB), Artibani Walter, Verona (IT) Battaglia Michele, Bari (IT), Bucci Stefano, Trieste (IT) Carini Marco, Firenze (IT), Carrieri Giuseppe, Foggia (IT) De Nunzio Cosimo, Roma (IT), Fandella Andrea, Treviso (IT) Ficarra Vincenzo, Messina (IT), Finazzi Agrò Enrico, Roma (IT) Franzese Corrado, Nola (IT), Gunelli Roberta, Forlì (IT) Kastner Christof, Cambridge (GB), Lapini Alberto, Firenze (IT) Miano Roberto, Roma (IT), Mirone Vincenzo, Napoli (IT) Montorsi Francesco, Milano (IT), Morgia Giuseppe, Catania (IT) Muller Stefan, Bonn (GE), Palazzo Silvano, Bari (IT) Pavlovich Christian, Baltimore, Maryland (USA) Pepe Pietro, Catania (IT), Rocco Bernardo, Modena (IT) Salomon George, Hamburg (GE) Schiavina Riccardo, Bologna (IT), Scattoni Vincenzo, Milano (IT) Volpe Alessandro, Novara (IT), Waltz Joachen, Marseille (FR)

Andrology Bettocchi Carlo, Bari (IT), Bitelli Marco, Roma (IT) Cai Tommaso, Trento (IT), Cormio Luigi, Foggia (IT) Fusco Ferdinando, Napoli (IT), Gontero Paolo, Torino (IT) Liguori Giovanni, Trieste (IT), Lotti Francesco, Firenze (IT) Pizzocaro Alessandro, Milano (IT), Trombetta Carlo, Trieste (IT)

Nephrology Boscutti Giuliano, Trieste (IT), D’Amelio Alessandro, Lecce (IT), Fiorini Fulvio, Rovigo (IT), Gesualdo Loreto, Bari (IT), Granata Antonio, Agrigento (IT), Ranghino Andrea, Ancona (IT)

Radiology Barozzi Libero, Bologna (IT), Bertolotto Michele, Trieste (IT) Giuseppetti Gian Marco, Ancona (IT), Giovagnoni Andrea, Ancona (IT), Valentino Massimo, Tolmezzo (IT)

Pathology Beltran Antonio Lopez, Lisbon (PT) Fiorentino Michelangelo, Bologna (IT) Liang Cheng, Indianapolis (USA), Montironi Rodolfo, Ancona (IT)

Bio-Medical Engineering Wijkstra Hessel, Eindhoven (NL) Advances in Urological Diagnosis and Imaging - 2020; 3, 1

Official Journal of S.I.E.U.N.

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Contents 3

AIMS and SCOPE “Advances in Urological Diagnosis and Imaging” (AUDI) has the purpose of promoting, sharing and favorite technical-scientific research on echography and imaging diagnosis, in diagnostic and terapeutical field of Urology, Andrology and Nefrology. AUDI publishes original articles, reviews, case reports, position papers, guidelines, editorials, abstracts and meeting proceedings. AUDI is Open Access at www.issuu.com Why Open Access? Because it shares science at your finger tips with no payment. It is a new approach to medical literature, offering accessible information to all readers, becoming a fundamental tool, improving innovation, efficiency and interaction among scientists.

A. Fandella, R. Gunelli,V. Scattoni, A. B. Galosi

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Review of the guidelines on prostatic biopsies – Guidance Document S.I.E.U.N. – AURO.it - SIUrO Pi-rads 3: biopsy yes - biopsy no. Are there any clinical or laboratory parameters that can help us? Psa density?

M. Barbera

mpMRI: standardization and reproducibility/ use of PI-RADS and proposal to standardize reporting. When the review (cross examination) of the mpMRI?

C. Gaudiano, R. Golfieri

Negative mpMRI:What’s next? What about the number of cores and the bioptic schemes? Update guidelines for the follow-up of patients with negative mpMRI

C. Maccagnano, R. Hurle, E. Scapaticci, L. Nava, G. N. Conti, V. Scattoni

Which biopsy strategy should be recommended in men with a positive prostate MRI:Targeted sampling alone or combined with systematic biopsy? G. Giannarini, A. R. Padhani

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Trends in MRI/TRUS Fusion Biopsy usage in clinical practice to early detection of Prostate Cancer: 2018 Survey by Prostatic Biopsy Italian Group A. Fandella, A. B. Galosi, R. Gunelli, P. Pepe

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Revision of the Italian Guidelines on Prostate Biopsy: An Update - 2020

Cognitive or visual biopsy role: Alone or a combination of techniques? M. Cevenini, A. Mottaran, A. Bertaccini, L. Bianchi, R. Schiavina

Cost-effectiveness of the MRI-based approach in naive patient and rebiopsy patient A. Mottaran, M. Cevenini, L. Bianchi, R. Schiavina, A. Bertaccini

Prostate biopsy and risk of sepsis: Which antibiotic prophylaxis? P. Pepe, A. Fandella

Focus on management of negative fusion biopsy on PI-RADS 4-5 prostatic lesions

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Advances in Urological Diagnosis and Imaging - 2020; 3, 1

REVIEW

Revision of the Italian Guidelines on Prostate Biopsy: An Update - 2020

Andrea Fandella 1, Roberta Gunelli 2, Vincenzo Scattoni 3, Andrea Galosi 4. on behalf of Prostate Biopsy Italian Group on update Guidelines* 1 2 3 4

Urology Private Clinic Rizzola, San Donà di Piave (Ve) Italy; Department of Urology, Morgagni Pierantoni Hospital, Forli, Italy; Unit of Urology, Division of Experimental Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy; Department of Urology, University Hospital “Ospedali Riuniti” and Polythecnic University of Marche Region, Ancona, Italy.

Prostate cancer (PCa) diagnostics have undergone a number of changes following efforts to reduce the detection rate of indolent prostate cancer and to increase the success rate for clinically significant prostate cancer (csPCA). The Panel performed a systematic analysis of the studies that have shifted our knowledge and the impact they have had on clinical practice under the Grade method in order to update Italian prostate biopsy guidelines. The introduction of multiparametric magnetic resonance imaging (mpMRI) have changed the landscape in PCa diagnostics, reducing the number of men who need biopsy, but increasing the need for accuracy in mapping the extension of prostate cancer. As mpMRI reporting has become more accurate in predicting PCa, biopsy techniques have also evolved towards lesion-targeted biopsies (when the PI-RADS score is between 3-5). Uncertainties remain regarding the preferred approach if only targeted biopsy, the need for systematic biopsies and in place of software ultrasound / MRI fusion or MRI on bore biopsy techniques with respect to “cognitive” fusion techniques. The targeted magnetic resonance biopsy offers greater diagnostic accuracy when compared with the current standard of care of transrectal ultrasound-guided systemic biopsy (TRUS), decreasing the overall number of biopsies needed, maintaining or improving the significant detection of prostate cancer and reducing the detection of clinically insignificant prostate cancer. The need to combine systematic prostate biopsy with MRI targeted biopsy is still debated. The use of magnetic resonance imaging - ultrasound fusion systems for targeting lesions is promising for optimizing significant cancer detection, but recent evidence suggests that extra-target cognitive biopsy sampling is still useful in detecting additional cancers. In the current state of knowledge, it is suggested to associate a systematic prostatic mapping with biopsies on the reported suspicious areas. This approach increases the diagnostic percent-

SUMMARY

age of clinically significant forms and decreases the number of biopsies to be performed. In patients with negative mpMRI, the decision to proceed with the biopsy will be made on the basis of clinical suspicion parameters (familiarity, PSA density, normograms).

KEY WORDS: Prostate cancer, mpMRI, biopsy, fusion biopsy.

The Panel consisted of Italian experts (17 urologists, one Pathologists, one radiologist and one methodologist). The panel was supported by the Association Urologist Italian (AURO.it) Italian Society of Uro-Oncology (SIURO) and the Italian Society of integrate diagnostic in Urology and Nephrology (SIEUN). The Commission defined the scope of the guidelines, the clinical questions, other relevant aspects (populations, interventions, outcomes, acceptable study designs etc.), and literature search strategies. A maximum of three experts were grouped for each topic after reviewing the literature from January 2015 to December 2019. The experts collected articles published in the English-language literature by performing both a computerized search using Medline, EMBASE and the Cochrane Library database, and manual search through the reference lists from each article. Studies in languages other than English were excluded due to lack of funding and resources for translation. Complete eligibility assessment was performed independently by two investigators who independently extracted data for each selected study using a standardized data extraction sheet defined a priori by the study team. Flow charts were defined for decision-making that described the current standard therapeutic pathways at Advances in Urological Diagnosis and Imaging - 2020; 3,1

A. Fandella, R. Gunelli, V. Scattoni, A. Galosi.

the commencement of work to update the guidelines; this enabled identification of decision points, and the definition of relevant clinical questions based on the Population, Intervention, Comparison, Outcome of interest, Type of study (PICOT) system (Tables 1-3). Outcomes were identified and their importance classified as important and essential (score 7-9), important but not essential (score 46), or not important (score 1-3) based on the votes of the core panel. On the basis of this classification, outcomes

were given greater or lesser consideration in the literature review and subsequent formulation of recommendations. For each intervention, the commission voted on the strength of recommendation (applying previously published rules) (1-3) and also the benefit/risk ratio (Table 3). A total of 1328 articles were identified by the literature search: 1290 of these were extracted, 879 were eliminated with reason, and 313 were finally assessed. Subsequently, the articles were evaluated using a systematic weighting and grading of the level of evidence accord-

Table 1. Controversies regarding prostate biopsy (Questions to be answered). 1. mpMRI: standardization and reproducibility / use of Pirads and proposal to standardize reporting, possibility of already providing a reference on the target lesion. MpMRI review: when? 2. mpMRI pz naive at all? Normograms value? Which? (validated for Italian population?) PSA Density, what pre MRI value? 3. Positive mpMRI only Target or Target + systematic? In the naive patient and in the re-biopsies 4. Negative mpMRI, what to do if negative mpMRI? If necessary biopsy which number of samples and which biopsy patterns? 5. Pirads 3 biopsy yes - biopsy no - are there any clinical or laboratory parameters that can help us? Psa density? 6. Role of visual or cognitive fusion? 7. Cost of the approach with mpMRI in patient naive, cost / benefit balance - same analysis in rebiopsy 8. What to do if mpMRI highlights Pirads 4 -5 and negative biopsy? MpMRI review? Remote repetition of mpMRI? Biopsy repeat? Target and systemic again - target only? change approach TR <> TP 9. Complications: is there evidence that the target approach reduces complications? What precautions to avoid sepsis? Which antibiotic prophylaxis? 10. Did the new classification of biopsy groups in severity groups impact the pathologist's way of reporting? Meaning of HGPIN and ASAP in the light of mpMRI? How to behave if ASAP and negative mpMRI? Table 2. Grade system used to rate the quality of evidence and the strength of recommendations.

Evidence level High quality Further research very unlikely to change confidence in estimate of effect Moderate quality Further research likely to have an important impact on confidence in estimate of effect and may change estimate Low quality Further research very likely to have an important impact on confidence in estimate of effect and likely to change estimate Very low quality Any estimate of effect is very uncertain Strength of recommendations Strongly positive The examined treatment is the first-choice therapeutic option (favorable benefit/risk ratio) Weakly positive Consider the examined therapeutic strategy as the first option, realizing there are alternatives that could have similar or more appropriate indications in different settings Weakly negative The examined treatment is not excluded, but its use is limited to carefully selected cases; the clinical decision must be thoroughly discussed and shared with the patient Strongly negative The examined treatment should be avoided (unfavorable benefit/risk ratio or lack of scientific evidence) Table 3. Definitions of the different benefit/risk ratios.

Risk/benefit ratio Definition Favorable Benefits clearly outweigh risks and burdens Uncertain Uncertain Uncertainty in the estimates of benefits, risks, and burden; benefits, risk, and burden may be closely balanced Unfavorable Risks clearly outweigh benefits and burdens

Advances in Urological Diagnosis and Imaging - 2020; 3,1

Revision of the Italian Guidelines on Prostate Biopsy: An Update - 2020

ing to the Grading of Recommendations Assessment, Development and Evaluation framework (GRADE) (4). The two investigators independently extracted data for each selected study using a standardized data extraction sheet defined a priori by the study team. Lastly, the final report was prepared according to the recommendations of the Conference on Guidelines Standardization (5). The final version was approved by the three Italian Scientific Societies that supported the panel. Conventional detection for prostate cancer (PCa) consists of digital rectal examination (DRE) and serum prostate specific antigen test (PSA), followed by prostate biopsy guided by transrectal ultrasound (TRUS). The role of multiparametric magnetic resonance imaging (mpMRI) has become increasingly important as reflected by the NCCN, American Urological Association (AUA) and European Association of Urology (UAE) recommendations (6-11). Specifically, the NCCN Clinical Practice Guidelines in Oncology for the early diagnosis of prostate cancer recommend that mpMRI be considered in men with indications for biopsy (e.g. elevated PSA) to reduce the number of men. biopsy which in turn will reduce the detection of indolent disease (and therefore the risks of over-detection and treatment) (7, 12). However, the guidelines emphasize that a negative mpMRI does not rule out the possibility of cancer and that biomarkers and / o PSA density should be considered when deciding whether to avoid a biopsy in a man with a negative mpMRI result. mpMRI has additional roles in the diagnosis of prostate cancer. First, mpMRI can be integrated with TRUS (MR-TRUS fusion) imaging which, as an increase in the detection rate of high-grade lesions (13-17). Recently published mpMRIbased prediction models have reduced biopsies not necessary despite being able to detect clinically significant diseases (18). Secondly, mpMRI plays a role in the initial staging of intermediate and high risk patients by detecting extra prostatic extension (EPE), invasion of the seminal vesicle and the involvement of the lymph nodes. mpMRI is also useful for selecting men suitable for nerve-sparing radical prostatectomy (19). Third, mpMRI can facilitate the exclusion of anterior carcinoma if the PSA level increases and the systematic results of the TRUS biopsy remain negative (20). In the radiological component of the biopsy workflow, several factors can reduce the quality of the image and the visibility of the lesion, including post biopsy hemorrhage, rectal gas, hip replacement or patient movement (21, 22). A collection of minimal patient preparation and technical specifications needed for a diagnostic study (22). However, it should be noted that despite these specifications, there remains a variability in image quality between centers (23). The location of the lesion can also affect detection. Not only are tumors within the transition zone less evident due to the large amount of signal heterogeneity associated with benign prostatic hyperplasia, but lesions of the apical peripheral area are lost more frequently (24-26). Smaller and less cellular lesions are less likely to be detected with mpMRI (25). Subsequently, the interpretation by the radiologist may also place a limitation on the use of mpMRI. A

study of 409 men whose mpMRI studies were read by 9 radiologists identified a marked variability in the PI-RADS distribution and yielded by the MR-TRUS biopsy. A wide range of 13% to 60% of men with a radiographically marked lesion with an equivocal or benign score (PIRADS score version 2 â&#x2030;¤3) had clinically significant carcinoma (27). Segmentation of prostate volume and injury can be a limitation. Prostate and tumor volumes are constantly underrepresented with mpMRI (28, 29). Positioning a TRUS device can cause significant gland deformation which increases the error in sampling the lesion, especially for smaller lesions. This phenomenon is becoming increasingly important, because many 3p mpMRI studies are performed and segmented without an end rectal device for MR-TRUS fusion (29, 30). MR-TRUS fusion biopsies have limitations that involve urologists performing the biopsy; as for radiologists, there is a variability in experience and an interindividual variability in the segmentation of prostate volumes by ultrasounds which are ultimately recorded with the MRI data set (31, 32). The technique can have intrinsic limits. A recent study found that clinically significant lesions in the lateral back and apical prostate were most commonly lost with MRTRUS fusion and that conventional TRUS most commonly missed clinically significant lesions in the anterior prostate (33). Together, these data are supported by studies confirming mpMRI guided biopsies may not detect index lesions 5% to 20% of the time (26, 34-36). The biopsy approach may be important, as MRI guided transperineal biopsy should have a significantly higher detection rate of clinically significant tumor than simple transrectal biopsy, which was mainly attributed to better sampling of the anterior prostate (37). These limitations must be taken into consideration in studies using MRTRUS biopsy specimens as the only means of confirming the presence of malignancy. These limitations introduce a potential problem in the clinical management of men with high PSA levels and negative mpMRI results who have not yet undergone prostate biopsy. Several retrospective studies have shown that clinically significant disease may be present despite the negative results of mpMRI. In addition, the evaluation of mpMRI depends on multiple factors, including the experience of the radiologist, the size of the lesion and the location of the lesion (26, 38-41). Although further prospective evidence is needed, these data support the use of other factors such as familiarity, nomograms and Psa density before excluding TRUS biopsy in this patient population with negative mpMRI (40, 41).

CONCLUSION During the work we wrote this programmatic document on the use of mpMRI of the prostate as a diagnostic means in the patient with suspicion of prostate cancer located in Italy. At present in subjects fit for treatment with clinical suspicion of prostate cancer, it is advisable to perform a multiparametric magnetic resonance imaging of the prostate, Advances in Urological Diagnosis and Imaging - 2020; 3,1

A. Fandella, R. Gunelli, V. Scattoni, A. Galosi.

where this is available with short execution times and adequate technology devices. This approach increases the diagnostic percentage of clinically significant forms and decreases the number of biopsies to be performed. In the current state of knowledge, it is suggested to associate a systematic prostatic mapping with biopsies on the reported suspicious areas. In patients with negative mpMRI, the decision to proceed with the biopsy will be made on the basis of clinical suspicion parameters (familiarity, PSA density, normograms)

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16. Rastinehad AR, Turkbey B, Salami SS, et al. Improving detection of clinically significant prostate cancer: magnetic resonance imaging/transrectal ultrasound fusion guided prostate biopsy. J Urol. 2014; 191:1749-1754. 17. Siddiqui MM, Rais-Bahrami S, Truong H, et al. Magnetic resonance imaging/ultrasound-fusion biopsy significantly upgrades prostate cancer versus systematic 12-core transrectal ultrasound biopsy. Eur Urol. 2013; 64:713-719. 18. Mehralivand S, Shih JH, Rais-Bahrami S, et al. A magnetic resonance imaging-based prediction model for prostate biopsy risk stratification. JAMA Oncol. 2018; 4:678-685. 19. Turkbey B, Mani H, Aras O, et al. Prostate cancer: can multiparametric MR imaging help identify patients who are candidates for active surveillance? Radiology. 2013; 268:144-152. 20. Dickinson L, Ahmed HU, Allen C, et al. Magnetic resonance imaging for the detection, localisation, and characterisation of prostate cancer: recommendations from a European consensus meeting. Eur Urol. 2011; 59:477-494. 21. Caglic I, Hansen NL, Slough RA, et al. Evaluating the effect of rectal distension on prostate multiparametric MRI image quality. Eur J Radiol. 2017; 90:174-180. 22. Weinreb JC, Barentsz JO, Choyke PL, et al. PI-RADS prostate imaging - reporting and data system: 2015, version 2. Eur Urol 2016; 69:16-40. 23. Caglic I, Barrett T. Optimising prostate mpMRI: prepare for success. Clin Radiol. 2019; 53(2):159-170. 24. Rosenkrantz AB, Kim S, Campbell N, et al. Transition zone prostate cancer: revisiting the role of multiparametric MRI at 3 T. AJR Am J Roentgenol. 2015; 204:W266-272. 25. Tan N, Margolis DJ, Lu DY, et al. Characteristics of detected and missed prostate cancer foci on 3-T multiparametric MRI using an endorectal coil correlated with whole-mount thin-section histopathology. AJR Am J Roentgenol. 2015; 205:W87-92. 26. Le JD, Tan N, Shkolyar E, et al. Multifocality and prostate cancer detection by multiparametric magnetic resonance imaging: correlation with whole-mount histopathology. Eur Urol. 2015; 67:569-576. 27. Sonn GA, Fan RE, Ghanouni P, et al. Prostate magnetic resonance imaging interpretation varies substantially across radiologists. Eur Urol Focus. 2019; 5(4):592-599. 28. Piert M, Shankar PR, Montgomery J, et al. Accuracy of tumor segmentation from multi-parametric prostate MRI and 18F-choline PET/CT for focal prostate cancer therapy applications. EJNMMI Res. 2018; 8:23. 29. Meyer C, Ma B, Kunju LP, et al. Challenges in accurate registration of 3-D medical imaging and histopathology in primary prostate cancer. EJNMMI Res. 2013; 40(Suppl 1):S72-78. 30. De Silva T, Fenster A, Bax J,et al. Quantification of prostate deformation due to needle insertion during TRUS-guided biopsy: comparison of hand-held and mechanically stabilized systems. Med Phys. 2011; 38:1718-1731. 31. Collins GN, Raab GM, Hehir M, et al. Reproducibility and observer variability of transrectal ultrasound measurements of prostatic volume. Ultrasound Med Biol. 1995; 21:1101-1105. 32. Zalesky M, Stejskal J, Adamcova V, et al. Inter-individual variability in MRI/TRUS fusion targeted biopsies in a first biopsy setting: bicentric prospective study. Eur Urol Suppl. 2018; 17:e712-713. 33. Schouten MG, van der Leest M, Pokorny M, et al. Why and where do we miss significant prostate cancer with multi-parametric magnetic resonance imaging followed by magnetic resonance-guided and transrectal ultrasound-guided biopsy in biopsy-naĂŻve men? Eur Urol. 2017; 71:896-903. 34. Russo F, Regge D, Armando E, et al. Detection of prostate cancer index lesions with multiparametric magnetic resonance imaging

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38. Bratan F, Niaf E, Melodelima C, et al. Influence of imaging and histological factors on prostate cancer detection and localisation on multiparametric MRI: a prospective study. Eur Radiol. 2013; 23:2019-2029. 39. Rosenkrantz AB, Mendrinos S, Babb JS, et al. Prostate cancer foci detected on multiparametric magnetic resonance imaging are histologically distinct from those not detected. J Urol. 2012; 187:20322038. 40. Panebianco V, Barchetti G, Simone G, et al. Negative multiparametric magnetic resonance imaging for prostate cancer: what’s next? Eur Urol. 2018; 74:48-54. 41. Branger N, Maubon T,Traumann M, et al. Is negative multiparametric magnetic resonance imaging really able to exclude significant prostate cancer? The real-life experience. BJU Int. 2017; 119:449-455.

*Prostate Biopsy Italian Group on update Guidelines: Michele Barbera (Urology Department - Sciacca Hospital - ASP Agrigento – Italy); Alessandro Bertaccini (Department of Urology, S. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy); Matteo Cevenini (Department of Urology, S. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy); Lucio Dell’Atti (Department of Urology, University Hospital “Ospedali Riuniti” and Polythecnic University of Marche Region, Ancona, Italy);

Andrea Fandella, Coordinator (Urology Private Clinic Rizzola San Donà di Piave (Ve), Italy); Michelangelo Fiorentino (Pathological Unit, Maggiore Hospital, University of Bologna, Italy); Carmine Franzese (Department of Urology, University Hospital “Ospedali Riuniti” and Polythecnic University of Marche Region, Ancona, Italy); Andrea Galosi (Department of Urology, University Hospital “Ospedali Riuniti” and Polythecnic University of Marche Region, Ancona, Italy); Caterina Gaudiano (Department of Diagnostic Medicine and Prevention Radiology Unit, S. Orsola Hospital, University of Bologna, Bologna, Italy); Gianluca Giannarini (Urology Unit, Academic Medical Centre, Santa Maria della Misericordia, Udine, Italy); Roberta Gunelli (Department of Urology, Morgagni Pierantoni Hospital, Forli, Italy); Alberto Lapini (Department of Urology, University of Florence, University Hospital, Firenze, Italy); Carmen Maccagnano (Division of Urology, ASST Lariana, Nuovo Ospedale Sant’Anna, Como, Italy); Pasquale Martino (Department of Urology, University of Bari, Bari, Italy); Angelo Mottaran (Department of Urology, S. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy); Alessio Papaveri (Department of Urology, University Hospital “Ospedali Riuniti” and Polythecnic University of Marche Region, Ancona, Italy); Giovanni Pappagallo (Epidemiology & Clinical Trials Office, General Hospital, Mirano (VE), Italy); Pietro Pepe (Urology Unit, Cannizzaro Hospital, Catania, Italy); Tiziana Pierangeli (Prostate Cancer Prevention Unit, IRCCS INRCA, Ancona, Italy); Vincenzo Scattoni (Unit of Urology, Division of Experimental Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy); Riccardo Schiavina (Department of Urology, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy).

CORRESPONDENCE Andrea Fandella Urology Private Clinic Rizzola San Donà di Piave VE, Italy. e-mail: afandella@libero.it

Advances in Urological Diagnosis and Imaging - 2020; 3,1

SURVEY

Trends in MRI/TRUS Fusion Biopsy usage in clinical practice to early detection of Prostate Cancer: 2018 Survey by Prostatic Biopsy Italian Group Andrea Fandella 1, Andrea B. Galosi 2, Roberta Gunelli 3, Pietro Pepe 4. on behalf of the Prostate Biopsy Italian Group on update Guidelines* 1 2 3 4

Department Department Department Department

of Urology, Casa di Cura Rizzola San Donà di Piave (Ve); Of Urology, Universtà Politecnica delle Marche, Ancona; of Urology, Ospedale Morgagni Pierantoni, Forlì; of Urology Canizzaro Hospital Catania.

SUMMARY

Objective. We examined urologists in Italy regarding their standard approach in 2018 to

prostate biopsy. Methods. The survey covered the year 2018 and was conducted at the 2nd meeting of Prostate Biopsy Italian Group (PBIG) on update Guidelines, during the XXVI National Congress Auro.it (Italian Association of Urology), held in Bologna in May 2019. The survey investigated 36 Urologist with proven experience and involved in prostate biopsy, who are coming from private, public and academic centers in Italy. Survey items queried respondents about their use in clinical practice of multiparametric magnetic resonance (mpMRI) and MR/TRUS fusion biopsy in 2018. The survey employed a standardized questionnaire approved by PBIG. Data were imported and analyzed in ANOVA and Chi square analyzes were used to assess variability in responses between demographic groups. Results. The survey is a compelling sample for the analysis, as it is representative of all centers (private, public and academic) centers of the Nation, with all Regions involved with the exception of Sardinia and Valle d'Aosta. The cut-off of PSA (prostate specific antigen) was recognized by all participant as 4.0 ng/ml and 3.0 using the Beckman and WHO samples respectively. Although antibiotic therapy was prescribed in all cases (96%), the concordance gradually reduced respectively about the molecule (80%), start of therapy (50%), and duration of therapy (30%). Transrectal approach was used by 75% of users compared to 25 of transperineal approach. All Urologist offer a sort of local anesthesia, but with different concentration and technique in relation to the approach used. General anaesthesia or sedation was infrequently used. MRI/TRUS guided biopsy is a standard of care in most of prostate biopsies. Data suggest that urologists support its use and are making efforts to introduce it into their practice. Several limitation of this survey including small number of par-

Advances in Urological Diagnosis and Imaging - 2020; 3,1

ticipant, selection bias, and referred to 2018. Conclusions. This representative survey, conducted in a sample of 31 Italian centers, before the introduction of EAU guideline in 2019, offers a snapshot of different use in clinical practice of MRimaging and MR/US fusion biopsy. Marked inhomogeneity emerged both in relation to the volume of the center and according to the clinical scenario. MRI/TRUS fusion biopsy is an emerging technology but is not carefully utilized and prescribed by urologist. It needs to be regulated and disciplined by guidelines, but their implementation into clinical practice requires significant resources.

KEY WORDS: Prostate cancer, Magnetic resonance imaging, Survey, MRI/TRUS fusion biopsy.

INTRODUCTION Prostate cancer (PCa) is the second most commonly diagnosed cancer among men, with an estimated 160,000 new cases reported in 2016 (1). Given this high incidence, it is necessary to develop highly sensitive and specific diagnostic and screening tests. Prostate specific antigen (PSA) screening has been used extensively in the detection of early stage malignancies, but has also increased the detection of benign lesions (2) sometimes leading to unnecessary invasive treatments and increasing healthcare costs (3). Men with a high PSA or an abnormal digital rectal exam suspected of having prostate cancer underwent biopsy, which traditionally is a standard extended sextant with random sampling of the entire prostate under the guidance of transrectal ultrasound (TRUS). While standard

Trends in MRI/TRUS Fusion Biopsy usage in clinical practice to early detection of Prostate Cancer: 2018 Survey by Prostatic Biopsy Italian Group

biopsy is an effective tool, without adequate prostate mapping, lesions of interest may be missed or incorrectly layered. The introduction of multiparametric magnetic resonance imaging (mpMRI) for prostate imaging in the last decade has helped identify potentially high-grade injuries (4), as well as reducing the risk of improvement (5). Even more recently, the combination of guided mpMRI/transrectal ultrasound (MRI/TRUS) platforms offers the possibility of superimposing mpMRI images in real time on TRUS and therefore performing more targeted biopsies. This targeting allows to diagnose more high-risk and fewer low-risk cases of PCa compared to the standard sextant biopsy (6, 7), as well as to track lesions over time with imaging or repeat the biopsy, through active surveillance (AS) (8-10). Multiparametric MRI/TRUS targeted biopsy is an emerging technology that has the potential to change the standard of care for the diagnosis and management of prostate cancer. Implementation of this technology is believed to have expanded in recent years, however quantitative analyzes are not available to describe these trends. To answer this question, we have developed a survey to be distributed to Italian urologists who perform prostate biopsy. The main objective of this study was to evaluate the ways in which urologists use mpMRI in their prostate cancer practices, as well as to evaluate attitudes regarding the role of MRI/TRUS fusion biopsy in daily clinical practice.

Table 1. Demographic distribution of survey respondents.

MATERIALS AND METHODS

by Italian Society of Urology (SIU) (12), and in particular does not contain a disproportionate percentage of urological oncologists who performed MRI/TRUS targeted prostate biopsies. The age of the respondents was included between 31-40 vs 41-50 vs 51-60 vs 61-70 vs more than 70 years old in the 19% vs 29% vs 31% vs 14% vs 7% of the cases, respectively. The 36 urologist come form 31 different urological center. Respondents were sub-categorized and analyzed by specialty, practice type, geographic region, and average number of prostate biopsies performed monthly.The absolute number, percentage of overall respondents, and population proportionate confidence intervals respectively, are displayed (Table 1) (Figures 1, 2). The approach to perform prostate (transrectal or transperineal) is reported in Figure 3.

QUESTIONNAIRE A survey of 20 queries was created during the 2nd meeting of the Prostate Biopsy Italian Group (PBIG) in charge of updating the Italian guidelines for prostate biopsies (11). The survey was distributed to all participant in the dedicated session on MR/US fusion biopsy during of the XXVI National Congress of the Association of Italian Urology (Auro.it), held in Bologna May 18, 2019. The survey investigated 36 Urologist with proven experience and involved in prostate biopsy, who are coming from 31 centers in Italy (private, public or academic). Survey items queried respondents about their use in clinical practice of multiparametric magnetic image resonance (mpMRI) and mpMRI/TRUS fusion biopsy in the previous year (2018). The survey employed a standardized questionnaire approved by PBIG. Data were imported and analyzed in ANOVA and Chi square analyzes were used to assess variability in responses between demographic groups.

RESULTS

Specialty

Respondents

General urology

67%

Urologic oncology

23%

Endourology

Male infertility/andrology Female urology/urodinamics

2% 2%

Categorization

Respondents

Academic center

29%

Private practice

General Hospital

39%

Multi-disciplinar Uro-Onco

18%

Geographic regions

Respondents

Northeast

23%

Northwest

29%

Centre

27%

South and Islands

21%

Figure 1. Working practice of participant Urologists.

Provenance

In total 36 of practicing urologists completed the survey representing urological centers and all Italian regions are represented with the exception of Sardinia and Valle D'Aosta. Respondents worked mainly in relatively small hospitals (60%) compared to larger ones, with over 400 beds (40%) and well represented by age, type of practice, geographical location and volume of prostate biopsies performed monthly (Table 1). The population of the survey participants shares a demographic distribution similar to the published demographic information provided annually Advances in Urological Diagnosis and Imaging - 2020; 3,1

A. Fandella, A.B. Galosi, R. Gunelli, P. Pepe. Figure 2. Number of biopsies performed by the center, to identify high, medium and low volume centers/operator.

How often do you prescribe MR imaging before the first Biopsy?

Number of biopsies performed/year

In naïve-biopsy patients, Urologist responded they require a MR always (4%), in most of cases (18%), in half of cases (4%), in less than half of case (21%), infrequently (21%), and seldom (32%) (Figure 4). As surprising data of the questionnaire is that there is a dichotomy: only 22% of urologists ask for mpMRI in more than half of naïve cases (Figure 5). Overall, 86% of respondents currently use magnetic resonance imaging in some way in their practice between naive patients and repeat biopsies. How often do you prescribe MR imaging before the repeated Biopsy? In patients who had a previous negative biopsy, Urologist responded they require a MR always (35%), in most of cases (15%), in more than half of cases (19%), in about half of case (12%), infrequently (8%), and seldom (11%) (Figure 4). Globally, 69% of urologists perform mpMRI in more than 80% of cases before repeat biopsy, 31% require

Figure 3. The approach used to perform prostate biopsy: transrectal vs transperineal.

Transrectal towards Transperineal

Figure 4. Answers to the question “How often do you prescribe MR in Biopsy Naive patients?” Only 22% (4%+18%) require a MR imaging in 80% of cases. Most of Urologist require MR in less then 40% of patients biopsy naive, and finally 32% only in very selected patient 5-10% before the first biopsy.

mpMRI in Naive patients

Advances in Urological Diagnosis and Imaging - 2020; 3,1

Figures 5a and 5b. Answers splitted (5A) and grouped (5b) to the question “How often do you prescribe MR imaging before repeated Biopsy?” Surprisingly 32% of responders require MR in 10 up to 50% of cases, whereas 34% of responders requires MR in most of 50 and 90%, and 35% in all cases before a repeated biopsy.

mpMRI at Rebiopsy

mpMRI before a Rebiopsy

Trends in MRI/TRUS Fusion Biopsy usage in clinical practice to early detection of Prostate Cancer: 2018 Survey by Prostatic Biopsy Italian Group Figure 6. Percentage of centers with a Radiologist who is dedicated most of prostate MR.

Urology dedicated radiologist

it in less than 50% of cases (Figures 6, 7). Fusion biopsy is utilized or shared by 82% of respondents, but only 41% used the software based technology while the 41% used the cognitive method only. Therefore almost 60% of centers do not have any computerized platform to perform MR/US fusion biopsy and moreover 20% do not had any fusion biopsy device. Considering that EAU guidelines were released in March 2019, the Italian situation is lacking about the equipment at the moment of the survey (May 2019). What is missing to perform the fusion biopsy?

Figure 7. Percentage of centers with a Pathologist who is dedicated to the study of urological pathology.

Pathologist dedicated to urological pathology

Figure 8. Percentage of the centers equipped with fusion software based device (41%), while 41% use cognitive method only, and 18% do not use any fusion technique.

Which Target biopsy technique

Urologists who did not have the resources to perform software based system to fusion biopsies were therefore asked to list specific difficulties to have this technology. Sixty-nine percent of respondents cited costs as the principal reason to implementation, and 36% indicated others reasons (staff, organization, etc.). Only 52% of the centers have a dedicated radiologist dedicated to prostate imaging MR in collaboration with urology unit (Figure 8). The lack of adequate facilities is marked by the fact that only 63% of the centers have a dedicated reference pathologist. The introduction of new technologies into clinical practice requires significant resources. Financial and healthcare efforts are needed to overcome problems and allow for the application of guidelines. The survey shows that only the 41% (37 plus 4%) of the centers own the software-based fusion instrumentation, 41% use the cognitive method, 18% use only the modified sextant technique. About 70% of urologists from academic/public centers had necessary resources to perform MRI/TRUS targeted biopsies, compared to 60% in private multi-specialty groups, 53% in private group studies and 35% in small surgeries (p = 0.002). Most respondents believe there is sufficient evidence to use MRI/TRUS fusion device as a standard of care in all prostate biopsies, while 69% believe that mpMRI evaluation should be reserved for more selected cases such as men with high PSA and previous negative biopsies. Only few (10%) believe that there is currently insufficient evidence to change practice from standard extended sextant biopsy. Finally, participants were asked if biopsies guided by MRI/TRUS increase their confidence that patients with suspected prostate cancer are appropriately stratified into risk assessment groups; 36% of respondents report a significant increase in confidence, a moderate increase of 38%, a minimum increase of 21% and 6% no change of confidence with the MRI / US biopsy. Does software-based fusion biopsy increased their confidence and accuracy? 36% of respondents report a significant increase in confidence, a moderate increase of 38%, a minimum increase of 21% and 6% no change of confidence with the MRI/TRUS biopsy. Within the subpopulations of the respondents, the urologists of the academic centers demonstrated the maximum use of the targeted fusion biopsy (71%). The results suggest that this is due to increased resources and investment in research. Advances in Urological Diagnosis and Imaging - 2020; 3,1

A. Fandella, A.B. Galosi, R. Gunelli, P. Pepe.

DISCUSSION

REFERENCES

Only 55% of respondents used MRI/TRUS device as a standard of care in all prostate biopsies as suggested by 2019 EAU guidelines. The others (45%) believe that should be reserved in selected cases such as high PSA and previous negative biopsies. However there are still few urologist (12%) who preferred systematic extended biopsy. A literature review cited mixed results when studying the economics surrounding MRI/TRUS fusion biopsies; anyway the initial cost of MRI and fusion platforms should be evaluated in regular screening for a disease as prevalent as prostate cancer before widespread use is possible (13, 14). While attitudes towards the implementation of the MRI/ TRUS guided biopsy are generally positive, there are some reservations about its use in real life worldwide. Most respondents believe that MRI should be reserved for selected cases such as men with previous negative biopsies in 2018 practice and not as standard of care in all patients. This statement agree with the 2018 EAU guidelines, but the 2019 edition extended also to biopsy naïve the fusion biopsy. Randomized studies with good level of evidence support this statements (15-17). This survey has several limitations. Since the survey was administered during a course, there may have been some selection errors introduced in terms of those who chose to participate, in particular urologist oncologists who could see more cases of prostate cancer and, therefore, be more familiar or have a more favorable opinion of mpMRI/TRUS targeted biopsy. In addition, like any survey, participants' responses were limited to the choices available. The lack of data from Valle d’Aosta and Sardinia which reflect less than 7% of the Italian population should not invalidate the questionnaire data which of course has only a cognitive value and can help implement clinical practice.The survey covered the year before the introduction of EAU guidelines in 2019.

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017; 67:7-30. 2. Lu-Yao GL, Albertsen PC, Moore DF, et al. Outcomes of localized prostate cancer following conservative management. JAMA. 2009; 302:1202-1209. 3. Shen X, Kumar P. Trade-off between treatment of early prostate cancer and incidence of advanced prostate cancer in the prostate screening era. J Urol. 2016; 195:1397-1402. 4. Kitajima K, Kaji Y, Fukabori Y, et al. Prostate cancer detection with 3 T MRI: comparison of diffusion-weighted imaging and dynamic contrast-enhanced MRI in combination with T2-weighted imaging. J Magn Reson Imaging. 2010; 31:625-631. 5. Rais-Bahrami S, Siddiqui MM, Turkbey B, et al. Utility of multiparametric magnetic resonance imaging suspicion levels for detecting prostate cancer. J Urol. 2013; 190:1721-1727. 6. Siddiqui MM, Rais-Bahrami S, Turkbey B, et al. Comparison of MR/Ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA. 2015; 313:390-397. 7. Meng X, Rosenkrantz AB, Mendhiratta N, et al. Relationship between prebiopsy multiparametric magnetic resonance imaging (MRI), biopsy indication, and MRI-ultrasound fusion-targeted prostate biopsy outcomes. Eur Urol. 2016; 69:512-517. 8. Tran GN, Leapman MS, Nguyen HG, et al. Magnetic resonance imaging-ultrasound fusion biopsy during prostate cancer active surveillance. Eur Urol. 2017; 72:275-281. 9. Ouzzane A, Renard-Penna R, Marliere F, et al. Magnetic resonance imaging targeted biopsy improves selection of patients considered for active surveillance for clinically low risk prostate cancer based on systematic biopsies. J Urol. 2015; 194:350-356. 10. Pepe P, Garufi A, Priolo GD, et al. Is it Time to Perform Only Magnetic Resonance Imaging Targeted Cores? Our Experience with 1,032 Men Who Underwent Prostate Biopsy. J Urol. 2018; 200:774778. 11. Fandella A, Galosi AB, et al. Revision of the Italian guidelines for prostate biopsy in order to be uptodate for 2020. What we have done. Advances Urological Diagnosis Imaging. 2020; 1:1-5. 12. SIU Roster Soci [www.siu.it] - Società Italiana di Urologia.

CONCLUSIONS There are regional and practical variations in the adaptation of this technology. While there are some reservations about the use of MRI/TRUS fusion biopsy for all men with suspected prostate cancer, the data suggest that urologists support it and are making efforts to introduce fusion targeted biopsy into their practice. This representative survey, conducted in a sample of 31 Italian centers, before the introduction of EAU guideline in 2019, offers a snapshot of different use in clinical practice of MRimaging and MR/US fusion biopsy. Marked inhomogeneity emerged both in relation to the volume of the center and according to the clinical scenario. MRI/TRUS fusion biopsy is an emerging technology but is not carefully utilized and prescribed by urologist. It needs to be regulated and disciplined by guidelines. Financial and healthcare efforts should be considered to let the application of guidelines.

Advances in Urological Diagnosis and Imaging - 2020; 3,1

13. Manley BJ, Brockman JA, Raup VT, et al. Prostate MRI: a national survey of urologist's attitudes and perceptions. Int Braz J Urol. 2016; 42:464-471. 14. Pepe P, Pepe G, Pepe L, et al. Cost-effectiveness of Multiparametric MRI in 800 Men Submitted to Repeat Prostate Biopsy: Results of a Public Health Model. Anticancer Res. 2018; 38:2395-2398. 15. Hutchinson RC, Costa DN, Lotan Y. The economic effect of using magnetic resonance imaging and magnetic resonance ultrasound fusion biopsy for prostate cancer diagnosis. Urol Oncol. 2016; 34:296-302. 16. Brock M, Löppenberg B, Roghmann F, et al. Impact of real-time elastography on magnetic resonance imaging/ultrasound fusion guided biopsy in patients with prior negative prostate biopsies. J Urol. 2015; 193:1191-1197. 17. Sonn GA, Chang E, Natarajan S, et al. Value of targeted prostate biopsy using magnetic resonance-ultrasound fusion in men with prior negative biopsy and elevated prostate-specific antigen. Eur Urol. 2014; 65:809-815.

Trends in MRI/TRUS Fusion Biopsy usage in clinical practice to early detection of Prostate Cancer: 2018 Survey by Prostatic Biopsy Italian Group

CORRESPONDENCE Andrea B. Galosi, MD, PhD Clinica Urologica, Università Politecnica delle Marche Azienda Ospedaliero-Universitaria "Ospedali Riuniti" Ancona, Italy e-mail: a.b.galosi@univpm.it Cell: +39 3388144573

Advances in Urological Diagnosis and Imaging - 2020; 3,1

REVIEW

Multiparametric magnetic resonance imaging (mp-MRI) is becoming an increasingly important diagnostic tool for prostate cancer. Little attention has been paid to the management of indeterminate mp-MRI results until now. Indeed the PIRADS score 3 imposes adjustments for the decision of biopsy or re-biopsy. The exclusive use of imaging is not sufficient as in scores 4 and 5. It is necessary to resort to some parameters such as PSA density (PSAD) or PSA age - volume (PSA AV) to know optimally who is most suitable for prostate biopsy.

SUMMARY

KEY WORDS: PIRADS 3, PSA Age-Volume, PSA density.

The sensitivity of resonance in recognizing a clinically significant prostate adenocarcinoma (Pca) is currently around 90% and this value is progressively increasing with the development of new technologies; this means that only 1 in 10 patients with cancer is a false negative. The high negative predictive value of the method (94%) can allow, in case of a negative test result, to avoid - at least at first prostate biopsy. However, in case of positive multiparametric resonance, the patient will have to undergo a prostate biopsy. Thanks to modern images fusion methods images, obtained both in resonance and with ultrasound, the biopsy will be more precise and less invasive compared to the old prostate biopsy protocols with random sampling. Referring to the classification of the Prostate Imaging Reporting and Data System (PI-RADS), the score 1 and 2 indicate a benign lesion, the score 3 (gray area) suggests a follow-up or new study that must be adapted to the patient's characteristics, the values 4 and 5 indicate a strong risk, therefore the patient should be sent for histological study by biopsy.

Advances in Urological Diagnosis and Imaging - 2020; 3,1

Indeed, PI-RADS 3 scores are considered doubtful. In these cases, the decision to perform the biopsy also depends on the other risk factors (such as the PSA value or rectal exploration findings). The PI-RADS 3 lesion site may also have some weight: lower cancer incidence in the transition zone. Currently - prudently - all patients with a PIRADS 3 area are generally undergo to prostate biopsy. In a UK study (1) they included 168 patients, all with 3 mpMRI score: 73 (43%) chose biopsy after mpMRI and 95 (57%) chose PSA monitoring and subsequent mpMRI at 6-12 months. The overall percentage of men with clinically significant carcinoma detected was 14% (23/168). The cancer risk profile identified in the initial surveillance group was similar to that identified in the immediate biopsy group. The limits of the study include short follow-up. But to decrease the number of unnecessary biopsies of patients with this score other literature can helps us. In literature, the various papers cite the need to use the PSA Density (PSAD) as an added value to score 3 in order to decide to do the biopsy (2); but also the value of the PSA Age Volume (PSA-AV) (3). In a recent Chinese observational study (3) to improve the detection of prostate cancer (PCa), version 2 of PIRADS and PSA-AV was combined, especially among patients in the gray area with a score of 3 and patients with PSA t from 4 to 10 ng/mL. The 357 patients were enrolled in this study. The PI-RADS v2 scoring system was used to represent the features of multiparametric magnetic resonance imaging (mpMRI). The PI-RADS v2 score 3 and the PSAt from 4 to 10 ng/mL were defined as gray area in the detection of the PCa. The PSA-AV formula is: the patient's age multiplied by the volume of the prostate and divided by the PSAt level (cutoff for biopsy <250).

Pi-rads 3: biopsy yes - biopsy no. Are there any clinical or laboratory parameters that can help us? Psa density?

A total of 174 (48.7%) had benign prostatic hyperplasia, 183 (51.3%) had PCa. The results showed that PI-RADS v2, PSAt and PSA-AV were significant independent predictors of prostate cancer. The PI-RADS v2 score ≥4 could detect PCa with a percentage of 82.1%. In serum PSAt≥10 ng/mL could detect PCa with a percentage of 66.2%, PSAD≥0.15 ng/mL/cc with a percentage of 62.8% and PSA-AV <250 with a rate of 83.5% (137 PCa / 164 PSAAV <250). The combination with PSA-AV <250, in patients with PSAT from 4 to 10 ng/ml could improve detection from 36.0% to 81%; those with PI-RADS v2 and score 3 and bioptized without calculating the predictors above: from 28.6% up to 60.0%. PI-RADS v2 and PSA-AV are faithful variables for the detection of PCa. For patients in the gray areas of PI-RADS v2 and PSAT, the PSA-AV can improve the detection rate of PCa. Instead, the combination of PIRADS v2 and PSAD scores (2, 3) can aid in decision-making before prostate biopsy and in follow-up strategy in biopsy-naïve patients. Patients with a PIRADS v2 score of ≤ 3 and a PSAD <0.15 ng/mL/cc can avoid unnecessary biopsies. But not everyone agrees with the 0.15 PSAD cut-off; in fact other literature drops the cut-off to 0.13 since from 0.13 to 0.29 (median 0.19) there are significant cancers (4). Do I need to perform follow-up MRI for PIRADS 3 lesions? (5). The use of PSAD combined with multiparametric magnetic resonance imaging has improved the negative predictive value of PIRADS increasing the chance to exclude a significant prostate cancer; around 20% of unnecessary biopsies could be safely avoided (6). However, a further stratification in PIRADS 3 and PSAD lesions <0.15 ng/mL could lead to a 36% reduction in the targeted targeted biopsy in this category, without losing any updates (7). The concept of Pirads 3 should also be stressed, which now, with PIRADS version 2.1, becomes PIRADS 4, by decreasing diffusion and increasing hypointensity in T2; and negative PIRADS 4 (8) at a second biopsy indicate a 13.6% of disease.

REFERENCES 1. Van der Sar ECA, Kasivisvanathan V, Brizmohun M, et al. Management of Radiologically Indeterminate Magnetic Resonance Imaging Signals in Men at Risk of Prostate Cancer. Eur Urol Focus. 2019; 5(1):62-68. 2. Washino S, Okochi T, Saito K, et al. Combination of prostate imaging reporting and data system (PI-RADS) score and prostate-specific antigen (PSA) density predicts biopsy outcome in prostate biopsy naïve patients. BJU Int. 2017; 119(2):225-233. 3. Yuan-Fei Lu, MDa, Qian Zhang, et al. Improving the detection rate of prostate cancer in the gray zone of PI-RADS v2 and serum tPSA by using prostate-specific antigen–age volume, Medicine. 2019; 98:26(e16289). 4. Brizmohun Appayya M, Sidhu HS, Dikaios N, et al. Characterizing indeterminate (Likert-score 3/5) peripheral zone prostate lesions with PSA density, PI-RADS scoring and qualitative descriptors on multiparametric MRI Br J Radiol. 2018; 91(1083):20170645. 5. Hauth E, Jaeger H, Hohmuth H, Beer M. Follow-up MR imaging of PI-RADS 3 and PI-RADS 4 prostate lesions. Clin Imaging. 2017; 43:64-68. 6. Distler FA, Radtke JP, Bonekamp D, et al. The Value of PSA Density in Combination with PI-RADS™ for the Accuracy of Prostate Cancer Prediction. J Urol. 2017; 198(3):575-582. 7. Schoots IG, Osses DF, Drost FH, et al. Reduction of MRI-targeted biopsies in men with low-risk prostate cancer on active surveillance by stratifying to PI-RADS and PSA-density, with different thresholds for significant disease. Transl Androl Urol. 2018; 7(1):132-144. 8. Pepe P, Garufi A, Priolo GD, et al. Early Second Round Targeted Biopsy of PI-RADS Score 3 or 4 in 256 Men With Persistent Suspicion of Prostate Cancer. In Vivo. 2019; 33(3):897-901.

CONCLUSIONS In conclusion, to improve the decision-making process on the execution or not of the biopsy in subjects with PIRADS 3 score at mpMRI, it would be necessary to: • Standardize reporting to have a unique PIRADS 3 as much as possible using multiple expert readers; • Agree on the PSA density value <0.13 or <0.15; • Use the PSA-AV <250; • Use of the PSA F / PSA T ratio as a density subgroup.

CORRESPONDENCE Michele Barbera Urology Department - Sciacca Hospital ASP Agrigento - Sicily – Italy e-mail: barbera.mic@gmail.com

Advances in Urological Diagnosis and Imaging - 2020; 3,1

REVIEW

mpMRI: standardization and reproducibility/use of PI-RADS and proposal to standardize reporting. When the review (cross examination) of the mpMRI?

Caterina Gaudiano, Rita Golfieri. Radiology Unit, Department of Diagnostic Medicine and Prevention, Santâ&#x20AC;&#x2122;Orsola Hospital, Bologna, Italy.

In recent years, multiparametric Magnetic Resonance Imaging (mpMRI) of the prostate has become a fundamental tool for evaluating patients with prostate cancer, demonstrating a high ability in detecting clinically significant tumours in many studies, recently also in the context of important multicentre trials. The European Society of Urogenital Radiology (ESUR) has produced the PIRADS (Prostate Imaging Reporting and Data System) guidelines to allow the standardisation of the execution, reading and reporting of this examination, also defining the minimum technical requirements for a high-quality study. Despite all these efforts, this examination still suffers from high heterogeneity in both execution and reading with reduced reproducibility of the results and reduced interobserver agreement which makes it still difficult to use in daily practice. The English-language literature from January 2015 to December 2019 was reviewed to evaluate the reproducibility of the results and the interobserver agreement, and to define the usefulness and applicability of the review of the mpMRI images by expert readers. The main studies present in the literature show great variability of the interobserver level of concordance which, in the majority of cases, is moderate-low. The review of the examinations by expert radiologists can improve the results in terms of sensitivity, specificity, negative predictive value and positive predictive value; however, the few papers present in the literature do not allow clarifying as to when and how this should be carried out.

SUMMARY

KEY WORDS: :multiparametric Magnetic Resonance Imaging; prostate cancer; PIRADS score; ESUR guidelines; inter-observer agreement

Since the first application of Magnetic Resonance Imaging (MRI) in studying the prostate, there has been the need to standardise an examination which could be carried out in very different ways. Nowadays, standardisation entails adherence to the PIRADS (Prostate Imaging Reporting

Advances in Urological Diagnosis and Imaging - 2020; 3,1

and Data System) guidelines as defined by the ESUR (European Society of Urogenital Radiology) which aim to identify and propose the most correct methods of (a) the execution of the examination (definition of the minimum technical requirements, sequences and acquisition parameters); (b) image analysis and (c) reporting by means of formulation of the PIRADS score. The ESUR guidelines were released in a first version in 2012 (PIRADS version 1) and were subsequently revised in 2014 (PIRADS version 2) and in 2019 (PIRADS version 2.1) (1-3). For the examination, the ESUR guidelines recommend the use of scanners with a high magnetic field; 1.5 Tesla or 3 Tesla devices have produced equivalent results although the latter is preferred by the majority of authors. As for the use of the endorectal coil, this is considered not to be essential on equipment with surface coils (phased array) with a number of channels â&#x2030;Ľ 16 while it is considered indispensable in other cases. The T2-weighted, DWI (Diffusion Weighted Imaging) and DCE (Dynamic Contrast Enhanced) sequences were necessary in the context of the multiparametric protocol; many studies have evaluated the effectiveness of the biparametric protocol, but there is still not enough evidence for its routine use. For the image analysis, the reading of each sequence according to the indications of the PIRADS is encouraged. For the examination reporting, it is suggested to use the conclusions by means of the PIRADS score for each lesion detected. The PIRADS guidelines provide an anatomical scheme of the prostate with well-defined sectors useful for indicating the site of the lesion; its use as an attachment to the report is encouraged in order to simplify understanding the mpMRI findings and to assist in biopsy execution. However, there is no obligation to use this scheme which, therefore, has not been universally adopted. In recent years, the use of the mpMRI and the PIRADS in the detection of clinically significant prostate cancer (csPCa) has been validated by several studies and recent meta-analyses (Table 1).

mpMRI: standardization and reproducibility/use of PI-RADS and proposal to standardize reporting. When the review (cross examination) of the mpMRI? Table 1. Results of the main meta-analyses regarding the capability of multiparametric Magnetic Resonance Imaging (mpMRI) in the detection of clinically significant prostate cancer.

Studies

mpMRI

Sensitivity

Specificity

NPV

PPV

de Rooij M, et al (4)

Likert scale

0.74 (95% CI, 0.66–0.81)

0.88 (95% CI, 0.82 –0.92)

0.65-0.94

0.31-0.95

Hamoen EHJ, et al (5)

PI-RADS v1

0.78 (95% CI, 0.70–0.84)

0.79 (95% CI, 0.68–0.86)

0.58-0.95

Zhang L, et al (6)

PI-RADS v2

0.85 (95% CI, 0.78–0.91)

0.71 (95% CI, 0.60–0.80)

0.26-0.92

0.54-0.92

Table 2. Stratification of the probability of clinically significant prostate cancer (csPCa) in the different categories of the Prostate Imaging Reporting and Data System (PIRADS) among the main studies published.

Studies

No. of patients

Probability of csPCa in the PIRADS categories PIRADS 1

PIRADS 2 20%

PIRADS 3

PIRADS 4

Hansen NL, et al (8)

807

Mehralivand S, et al (9)

339

10%

12%

22%

72%

Greer MD, et al (10)

163

16%

33%

71%

91%

The comparison between the two versions has shown that version 2 of the PIRADS improves the assessment of the transition zone which is still today difficult to evaluate (Figures 1, 2) while version 1 still allows better assessment of the peripheral zone (Figures 3, 4) (7). Table 2 shows the stratification of the probability of csPCa in the different categories of the PIRADS among the principal studies published. Concerning the two questions mentioned above, the English-language literature from January 2015 to December 2019 was reviewed, using the Medline, Embase and Cochrane Library databases with the followings key words “multiparametric Magnetic Resonance Imaging”, “Prostate cancer”, “PIRADS score”, “Likert Scale”, “standardisation”, “reproducibility”, “interobserver agreement”, “review” and “re-evaluation”. In recent years, several studies have assessed the reproducibility and interobserver agreement of mpMRI, an examination still very dependent on the experience of the reader. A study by Muller BG et al. in 2015 (11), which included five independent readers of various experience comparing a homemade score with the PIRADS score, confirmed the high diagnostic performance of the mpMRI but with a moderate inter-reader agreement level (concordance coefficient of 0.47), confirming the results of previous studies (12, 13). More recent papers have shown medium to high interobserver agreement levels with a coefficient of concordance of 0.72 (14) or poorer with a coefficient of 0.24 (15). These studies have confirmed the usefulness of the PIRADS as a main tool for the standardisation of reporting mpMRI examinations; however, both versions of the PIRADS are burdened by the moderate reproducibility of the results, still highly influenced by the experience of the radiologist.

31%

PIRADS 5 71%

Figure 1. A PIRADS 5 lesion of the transition zone. (A) Axial T2weighted sequence: hypointense area with indistinct margins and drop-like morphology of the transition zone in the median anterior intermediate site with a diameter of > 1.5 cm (arrows). (B) Apparent diffusion coefficient (ADC) map: the lesion appears clearly hypointense due to the marked restriction of the diffusivity (arrows). Fusion biopsy showed the presence of a prostate tumour having a Gleason Score 3 + 4.

Figure 2. A PIRADS 3 lesion of the transition zone. (A) Axial T2weighted sequence: hypointense capsulated nodule of the transition zone in the anterior left paramedian intermediate site (arrow), with morphological appearance similar to a nodule of benign hypertrophy. (B) Apparent diffusion coefficient (ADC) map: the nodule appears clearly and heterogeneously hypointense due to the marked restriction of the diffusivity (arrow). A fusion biopsy showed the presence of a prostate tumour having a Gleason Score 3 + 3 and 3 + 4.

Advances in Urological Diagnosis and Imaging - 2020; 3,1

C. Gaudiano, R. Golfieri. Figure 3. A PIRADS 4 lesion of the peripheral zone. (A) Axial T2weighted sequence: hypointense nodule with regular margins of the peripheral zone in the right posterolateral intermediate site with a maximum diameter of 14 mm (arrow). (B) Apparent diffusion coefficient (ADC) map: the lesion appears clearly hypointense due to the marked restriction of the diffusivity (arrow). (C) Perfusion map: the lesion appears clearly hyperintense due to marked vascularisation as is also shown by the Intensity-Time perfusion curve (D). A fusion biopsy showed the presence of a prostate tumour having a Gleason Score 4 + 3.

Figure 4. A PIRADS 3 lesion of the peripheral zone. (A) Axial T2weighted sequence: blurred hypointense area with indistinct margins of the peripheral zone in the left posteromedial apical site (arrow). (B) Apparent diffusion coefficient (ADC) map: the lesion appears slightly hypointense due to discrete restriction of the diffusivity (arrow). (C) Perfusion map: the lesion appears moderately hyperintense due to the discrete vascularisation as also shown by the Intensity-Time perfusion curve (D). A fusion biopsy showed the presence of chronic exacerbated prostatitis.

Advances in Urological Diagnosis and Imaging - 2020; 3,1

Furthermore, the difficulty of reproducing the results of clinical trials in the daily clinical scenario has aroused great interest in the production of papers which report “real life” situations in which the scenarios of multiple readers of highly variable experience are reported, and compared the radiologists who work in peripheral centres with those who work in tertiary centres. One of these very recent studies (16) involved 409 patients, with a total of 503 lesions, and nine independent readers of various experience, reporting results which allowed food for thought: (1) the distribution of the PIRADS score varied between radiologists, in particular there was a significant variation in the detection of csPCa, and it was not clear whether this variation was due to differences in the patient population, the technical aspects or the interpretation of the results; (2) the correlation between the PIRADS score and the presence of cancer (of all tumours and of clinically significant tumours) is highly variable among the various radiologists; (3) the percentage of patients with a PIRADS score <3 (average 22%, range 12-30%) and those with PIRADS score <3 and a csPCa (average 24%, range 13–60%) was very variable among the various radiologists and (4) in the multivariate analysis, the factors which were significantly associated with csPCa were the PIRADS score, the history of Active Surveillance and the experience of the radiologist. If, on the one hand, these results, confirmed the PIRADS score to be one of the most powerful factors associated with the outcome of a biopsy, on the other hand, they suggested caution in extrapolating the results of published studies to one's daily reality. One of the main implications is represented by the variability of the results in the PIRADS score <3 categories, which make the universal adoption of the biopsy recommendations based on the results of studies, less secure. Regarding the review of mpMRI images, there are only a few studies in the literature which have evaluated the value of the re-evaluation of images by expert readers. The aim of the first study published in 2017 (17) was to assess the value of the second opinion on mpMRI examination by specialised uro-radiologists of a tertiary centre for the detection of csPCa in a transperineal fusion prostate biopsy. The first and second evaluation of the mpMRI of 158 patients performed in regional hospitals before the transperineal fusion biopsy, performed in a tertiary centre, for a period of 3 years, were collected and the positive predictive value (PPV) and the negative predictive value (NPV) were assessed for the detection of csPCa (Gleason score [GS] 7-10). The results of this study demonstrated: (1) a disagreement between the two assessments in 54% of cases; (2) the NPV of the re-evaluation was higher than the initial assessment (0.89 vs. 0.72 for GS 7-10; 0.97 vs. 0.84 for GS ≥ 4 + 3); (3) the PPV of the re-evaluation was higher than the initial evaluation and (4) in the case of doubtful findings, the PPV was not significantly different between the two assessments. The results of the study showed that mpMRI is more frequently considered negative in tertiary centres and that the rereading of the examinations by specialised uro-radiologists significantly increased the NPV and the PPV.

mpMRI: standardization and reproducibility/use of PI-RADS and proposal to standardize reporting. When the review (cross examination) of the mpMRI?

Considering these results, the authors suggested adopting extreme caution in the clinical decision-making process, in particular as to whether to avoid biopsy in patients with negative mpMRI or to perform only targeted sampling in the case of positive mpMRI. The second paper published in 2019 (18) assessed the added value of reviewing the mpMRI examinations to avoid unnecessary biopsies by reviewing 226 examinations, repeated in the case of inadequacy. If the re-reading showed the PIRADS findings ≥ 3, a targeted biopsy was performed and, for findings ≤ 2, a random biopsy was performed in the presence of high diagnostic suspicion; otherwise, the patients were sent to follow-up. The results of this study showed that approximately 11% of the re-evaluated examinations did not report the PIRADS score and that 11% of the same examinations were carried out suboptimally and/or without all the sequences required by the guidelines. The level of interobserver agreement between the two evaluations was very low (coefficient of concordance of 0.23). In 48% of cases, a change in patient management was demonstrated; in particular, 102 (51%) targeted biopsies were avoided and 72 (34.5%) patients were not sent to biopsy after reassessment of the mpMRI examinations.

CONCLUSIONS mpMRI represents a powerful diagnostic tool for the assessment of PCa and adherence to the PIRADS guidelines allows improvement in terms of the standardisation and reproducibility of the results. However, this examination is still burdened by reduced interobserver agreement, mainly due to the effect of the experience of the reader. These considerations have suggested caution in extrapolating the results of published studies to one’s daily reality. As a remedy for these difficulties, the few studies in the literature have suggested the usefulness of reviewing the mpMRI examinations by expert radiologists; however, there are no specific indications as to when this review should be carried out.

REFERENCES 1. Barentsz JO, Richenberg J, Clements R, et al. European Society of Urogenital Radiology. ESUR prostate MR guidelines 2012. Eur Radiol. 2012; 22(4):746-57. 2. Weinreb JC, Barentsz JO, Choyke PL, et al. PI-RADS Prostate Imaging - Reporting and Data System: 2015, Version 2. Eur Urol. 2016 ;69(1):16-40. 3. Turkbey B, Rosenkrantz AB, Haider MA, et al. Prostate Imaging Reporting and Data System Version 2.1: 2019 Update of Prostate Imaging Reporting and Data System Version 2. Eur Urol. 2019; 76(3):340-51.

Detection with Multiparametric Magnetic Resonance Imaging: A Diagnostic Meta-analysis. Eur Urol. 2015; 67(6):1112-21. 6. Zhang L, Tang M, Chen S, et al. A meta-analysis of use of Prostate Imaging Reporting and Data System Version 2 (PI-RADS V2) with multiparametric MR imaging for the detection of prostate cancer. Eur Radiol. 2017; 27(12):5204-14. 7. Polanec S, Helbich TH, Bickel H, et al. Head-to-head comparison of PIRADS v2 and PI-RADS v1. Eur J Radiol. 2016; 85(6):1125-31. 8. Hansen NL, Barrett T, Kesch C, et al. Multicentre evaluation of magnetic resonance imaging supported transperineal prostate biopsy in biopsy-naïve with suspicion of prostate cancer. BJU Int. 2018; 122(1):40-9. 9. Mehralivand S, Bednarova S, Shih JH, et al. Prospective evaluation of PIRADSTM Version 2 using the International Society of Urological Pathology Prostate Cancer Grade Group System. J Urol. 2017; 198(3):583-90. 10. Greer MD, Shih JH, Lay N, et al. Validation of the dominant sequence paradigm and role of Dynamic Contrast-enhanced Imaging in PI-RADS Version 2. Radiology. 2017; 285(3):859-69. 11. Muller BG, Shih JH, Sankineni S, et al. Prostate Cancer: interobserver agreement and accuracy with the revised Prostate Imaging Reporting and Data System at Multiparametric MR Imaging. Radiology. 2015; 277(3):741-50. 12. Rosenkrantz AB, Kim S, Lim RP, et al. Prostate cancer localization using multiparametric MR imaging: comparison of Prostate Imaging Reporting and Data System (PI-RADS) and Likert scales. Radiology. 2013; 269(2):482-92. 13. Schimmöller L, Quentin M, Arsov C, et al. Inter-reader agreement of the ESUR score for prostate MRI using in-bore MRI-guided biopsies as the reference standard. Eur Radiol. 2013; 23(11):3185-90. 14. Giannarini G, Girometti R, Crestani A, et al. A prospective accuracy study of Prostate Imaging Reporting and Data System Version 2 on Multiparametric Magnetic Resonance Imaging in detecting clinically significant prostate cancer with whole mount pathology. Urology. 2019; 123:191-7. 15. Smith CP, Harmon SA, Barrett T, et al. Intra- and interreader reproducibility of PI-RADSv2: A multireader study. J Magn Reson Imaging. 2019; 49(6):1694-1703. 16. Sonn GA, Fan RE, Ghanouni P, et al. Prostate Magnetic Resonance Imaging interpretation varies substantially across radiologists. Eur Urol Focus. 2019; 5(4):592-9. 17. Hansen NL, Koo BC, Gallagher FA, et al. Comparison of initial and tertiary centre second opinion reads of multiparametric magnetic resonance imaging of the prostate prior to repeat biopsy. Eur Radiol. 2017; 27(6):2259-66. 18. Luzzago S, Petralia G, Musi G, et al. Multiparametric-magnetic resonance imaging second opinion may reduce the number of unnecessary prostate biopsies. Time to improve radiologists’ training program? Clin Genitourin Cancer. 2019; 17(2):88-96.

CORRESPONDENCE Caterina Gaudiano, MD

4. de Rooij M, Hamoen EH, Fütterer JJ, et al. Accuracy of multiparametric MRI for prostate cancer detection: a meta-analysis. AJR Am J Roentgenol. 2014; 202(2):343-51.

Radiology Unit, Department of Diagnostic Medicine and Prevention

5. Hamoen EHJ, de Rooij M, Witjes JA, et al. Use of the Prostate Imaging Reporting and Data System (PI-RADS) for Prostate Cancer

Phone: +39 051 2142307

Sant’Orsola Hospital, Via Albertoni, 15 - 40138 Bologna, Italy E-mail: caterina.gaudiano@aosp.bo.it; caterina.gaudiano@gmail.com

Advances in Urological Diagnosis and Imaging - 2020; 3,1

REVIEW

Negative mpMRI: What’s next? What about the number of cores and the bioptic schemes? Update guidelines for the follow-up of patients with negative mpMRI Carmen Maccagnano 1, Rodolfo Hurle 2, Emanuele Scapaticci 3, Luciano Nava 3, Giario Natale Conti 1, Vincenzo Scattoni 4. 1

Department of Surgery, Division of Urology, ASST Lariana, Nuovo Ospedale Sant’Anna, San Fermo della Battaglia (CO), Italy; 2 Department of Urology, Istituto Clinico Humanitas IRCCS, Clinical and Research Hospital, Rozzano (MI), Italy; 3 Division of Urology, Humanitas San Pio X – Milano, Italy; 4 Department of Urology, San Raffaele Hospital, Vita-Salute University, Milan, Italy.

Objective. Updating guidelines about the follow-up of patients (pts) with negative multi-parametric Magnetic Resonance Imaging (mpMRI). Materials and methods. English-language literature review since 2010 up to December 2019, using Medline, Embase and the Cochrane Library database, with the following key words:”Multiparametric Magnetic Resonance”, “Prostate Cancer”, “Prostate Biopsy”, “Follow-up”, “PI-RADS 1”, “PI-RADS 2”, “Likert scale 1”, “Likert Scale 2”. The papers were evaluated according to the Grading of Recommendations Assessment, Development and Evaluation framework system. We also analyzed the 2019 Guidelines of different international scientific Societies. Results. We found several limits, partly due to mpMRI itself and the different phases of the exam, and partly due to literature definitions of diagnostic performances of the mpMRI, definitions of clinically significant prostate cancer (csPCa) and definition of negative predictive value (NPV) of mpMRI and of negative mpMRI itself. We also evidenced different guidelines according to the International Societies. The clinical suspicion and the ancillary Prostate Specific Antigen (PSA) tests play a fundamental role in the decision-making process (always shared with pts). In case of negative mpMRI a follow-up with regular PSA during the five years should be advised. mpMRI has to be repeated in case of 25% PSA increasing comparing to the previous PSA and, then, PBx has to be performed in case of PI-RADS ≥ 3. In case of repeated prostate biopsy (PBx), number and location of the cores have to be established according to PSA values, prostate volume, familiar history, comorbidities and life expectancy. Conclusions. These updated guidelines and recommendations are intended to assist physicians and pts in the decision making regarding follow-up after negative mpMRI.

SUMMARY

KEY WORDS: :Multiparametric Magnetic Resonance, Prostate Cancer, Prostate Biopsy, Follow-up, PI-RADS 1, PI-RADS 2, Likert scale 1, Likert Scale 2.

Advances in Urological Diagnosis and Imaging - 2020; 3,1

INTRODUCTION The traditional diagnostic criteria of prostate cancer (PCa) are based on PSA level, digital rectal examination (DRE), and systematic transrectal (TRUS)-12-core PBx. During the last decades, we have observed an overdiagnosis of indolent PCa, which provides no benefit to the patient, and an underdiagnosis of csPCa, which potentially harms pts. The introduction of mpMRI and US fusion–guided PBx has improved the detection of csPCa and reduced the detection of indolent PCa. As a matter of fact, the final aim of employing mpMRI in this context is saving from unnecessary PBx and associated morbidity (infections, sepsis, bleeding, pain, hospitalization), counterbalancing the costs of potentially missing a csPCa (1-8). The increasing application of mpMRI has lead to changing paradigms for all the categories of pts, especially those men who can avoid PBx if the mpMRI is considered negative, i.e. PI-RADS or Likert Score 1-2. After literature review and comparison with international scientific Societies guidelines, we propose the updated guidelines for the follow-up of pts with negative mpMRI.

MATERIALS AND

METHOD

We reviewed English-language literature review since 2010 up to December 2019, using Medline, Embase and the Cochrane Library database, with the key words: ”Multiparametric Magnetic Resonance”, “Prostate Cancer”, “Prostate Biopsy”, “Follow-up”, “PI-RADS 1”, “PIRADS 2”, “Likert scale 1”, “Likert Scale 2”. The papers were evaluated using a systematic weighting and grading of the level of evidence according to the Grading of Recommendations Assessment, Development and Evaluation framework system. We finally selected 57 papers according to the criteria reported in Table 1.

Negative mpMRI: What’s next? What about the number of cores and the bioptic schemes? Update guidelines for the follow-up of patients with negative mpMRI Table 1. References and selection criteria.

Total references

References regarding guidelines

References published before 2010 but considered in present paper

Articles effectively analyzed in 57 the paper Selection Criteria of articles

 Data about negative mpMRI and follow-up  Impact factor of the journal  Randomized Clinical Trials  Prospective Cohort Studies with follow-up  Retrospective Studies  Experts’ opinions

We also analyzed the 2019 Guidelines of the most important international scientific Societies: European Association of Urology (EAU), American Urological Association (AUA), National Comprehensive Cancer Network (NCCN), National Institute of Clinical Excellence (NICE).

RESULTS We found several limits, partly due to mpMRI itself and the different phases of the exam and partly due to literature definitions of different issues (see Table 2). They will be analyzed and discussed in the next session. The summary of 2019 guidelines of international scientific Societies is reported in Table 3. All the guidelines revealed limited long-term follow‑up evidence on the natural history of people with PI-RADS or Likert score <1-2. Additionally, they all underlined the importance of sharing decision with pts and the importance of other ancillary tests and clinical features such as familiar history, comorbidities and life expectancy (9-11) (Tables 3, 4).

DISCUSSION LITERARURE

CRITICAL ISSUUE

As reported in Table 2, mpMRI per se showed several limits, according to the different phase of the exam:

Table 2. Limits of both mpMRI and literature itself found during literature review.

mpMRI phases

Literature definitions

Images acquisition

Diagnostic performances of the mpMRI

Images interpretation

Definitions of csPCA

Fusion PBx

Definition of NPV of mpMRI Definition of negative mpMRI

1. Images acquisition: equipment and scanning protocols are different among the Institutions and the Radiologists (1.5 T vs 3.0 T, endorectal vs abdominal coil; differences about b-values) (12). 2. Images interpretation: the reader experience is extremely important to avoid false negative. As a matter of fact, mpMRI exams are more often called negative in subspecialist reads. Poor inter-reader reproducibility is common, in some case poor “intra-reader” variability can be evidenced (13). 3. Fusion PBx: mpMRI is increasingly being used to guide PBx, thanks to the high accuracy of mpMRI-targeted techniques (14, 15). Additionally, it is currently recommended to target lesions in pts suspected of harboring PCa despite negative PBx (16). Nevertheless, not all the urologists are able to integrate mpMRI during fusion PBx and this procedure requires a quite long learning curve, whose duration is still a matter of debate (17-22). Moreover, we found several literature limits. Above all, there is great variability in PCa prevalence; there are few data concerning the intermediate- and long-term followup of patients with negative mpMRI in contemporary literature (12, 23). 1. Diagnostic performances of the mpMRI: previous systematic reviews have been based on study designs that did not accurately capture target conditions and index or reference test definitions, leading to a number of biases and inaccurate findings. 2. Definitions of csPCA: the employment of Prostate Imaging Reporting Data System version2 (PIRADSv2) have improved predictions for csPCa, defined as lesions with a Gleason Score > 6 or diameter > 0.5 cm (24). Nevertheless, the established definitions of csPCa, based on histology from systematic PBx [such as Gleason grading or the International Society of Uropathology (ISUP) grade systems] cannot be always applied to results from the mpMRI pathway itself. As a matter of fact, some authors have used additional “non-histological” parameters like PSA, familial history, race, volume of cancer, age and comorbidities (25-28). In a meta-analysis of 13 studies totaling over 2000 pooled patients who underwent mpMRI scored via PIRADSv2, the overall sensitivity was 85% for csPCa with a specificity of 71%. Accuracy improved with more sophisticated imaging equipment (3.0 T and endorectal coil) and with increased reader experience. Nevertheless, there is significant uncertainty when a prostate lesion is scored on mpMRI as likely csPCa (i.e., PIRADS 4 or 5), but targeted prostate biopsy (TPBx) results are negative (29). In this context, Mehralivand et al. examined PIRADSv2 performance by stratifying the results according to PIRADS scores. Similarly to other studies, they found high falsepositive PCa Detection Rate (DR) for PIRADS 430(30, 31). Additionally, the separate multi-reader study by Rosenkrantz et al. suggest there is 10–15% of csPCa undetected by mpMRI and TPBx (32). 3. Definition of negative predictive value (NPV) of mpMRI: according to some Authors, the values of NPV are very high. Particularly, Villers et al. reported NPVs of 85% for foci >0.2 cm3 and 95% for foci >0.5cm3, comAdvances in Urological Diagnosis and Imaging - 2020; 3,1

C. Maccagnano, R. Hurle, E. Scapaticci, L. Nava, G. N. Conti, V. Scattoni. Table 3. Summary of Guidelines by different international scientific Societies about negative mpMRI Abbreviations: LE Level of Evidence; SR Strenght Rating

BIOPSY NAÏVE PATIENTS

PATIENTS WITH PRIOR NEGATIVE BIOPSY EUROPEAN ASSOCIATION OF UROLOGY https://uroweb.org/guideline/prostate-cancer/

“[…] When mpMRI is negative and clinical suspicion of prostate cancer is low, omit biopsy based on shared decision making with the patients.” (LE 2a, SR weak)

“[…] When mpMRI is negative and clinical suspicion of prostate cancer is high, perform systematic biopsy based on shared decision making with the patients.” (LE 2a, SR strong)

NATIONAL COMPREHENSIVE CANCER NETWORK https://nccn.org/store/ A negative mpMRI does not exclude the possibility of cancer. Then systematic biopsy should be performed. No indication about number and location of cores, but only about biopsy timing (not exceeding 12 months). Additionally, biomarkers and/or PSA density should be considered when deciding whether to avoid a biopsy in a man with a negative mpMRI result. AMERICAN UROLOGICAL ASSOCIATION (CONSENSUS STATEMENT OF THE AMERICAN UROLOGICAL ASSOCIATION & THE SOCIETY OF ABDOMINAL RADIOLOGY'S PROSTATE CANCER DISEASE-FOCUSED PANEL) https://www.auanet.org/guidelines/mri-of-the-prostate-sop In men with low risk mpMRI, (PI-RADS<2), ancillary markers may be of value to identify patients warranting repeat systematic Pbx.

Series that have incorporated mpMRI-targeted sampling in their repeat PBx scheme have consistently demonstrated increased DR relative to systematic sampling, unique DR among MRI-targeted cores, and consistent PCa DR, regardless of number of previous PBx sessions

NATIONAL INSTITITUTE OF CLINICAL EXCELLENCE https://www.nice.org.uk/guidance/ng131/chapter/Recommendations For people who have a raised PSA and mpMRI Likert score of 1 or 2, and who have not had a PBx, repeat PSA test at 3 to 6 months and offer PBx: 1.If there is a strong suspicion of Pca: PSA density greater than 0.15 ng/ml or PSA velocity greater than 0.75 ng/year; strong family history. 2. Taking into account their life expectancy and comorbidities. If the level of suspicion is low: 1.Discharge the person to primary care 2.Set a PSA level for primary care at which to re‑refer based on PSA density (0.15 ng/ml/ml) or velocity (0.75 ng/year); 3.Advise PSA follow‑up every 2 years

Table 4. Ancillary tests

Tests

References

PSA density

 Venderink W et al. Eur Urol 2018 (9)  Hansen NL et al. BJU Int 2018 (10)  Washino S et al. BJU Int 2017 (11)

PSA velocity Prostate Cancer Antigen 3 [PCA3] Prostate Health Index [PHI] 4Kscore (OPKO Health; Miami, FL)

pared with histopatho-logy (33). Subsequent studies reported a NPV for csPCa of 90% at 5-yr follow-up after initial negative mpMRI and of 99% in men undergoing mpMRI before standard PBx (34, 35). A recent meta-analysis showed that mpMRI has a median NPV of 88% for csPCa, for a median DR of csPCa of 33% (23). Conversely, some author reported lower NPV. For example, Filson et al reported an NPV of nMRI of 54%, with 16% of pts with csPCa (36). The retrospective study of Panebianco et al. showed mpMRI to be highly reliable in excluding csPCa in pts with previous negative

Advances in Urological Diagnosis and Imaging - 2020; 3,1

PBx. The authors reported that a 5% risk of developing a csPCa during follow-up, compared with a reported NPV of systematic PBx of 74% or lower, might be considered acceptable and clinically appropriate, and would suggest PSA monitoring rather than PBx in order to adequately follow-up pts (12). Nevertheless, the great variability in csPCa prevalence among the different cohorts (which directly influences NPV), the lack of standardization of the population referred to PBx and the variability of definitions of csPCa still remain important issues to be clarified. 4. Definition of negative mpMRI: some authors underlined that mpMRI is less accurate in the detection of all csPCa in a given patient, comparing to a good sensitivity on a per-patient basis (37-39). In addition to missing cancers, studies have also shown that mpMRI can lead to underestimation of the PCa volume (40-44). Finally, the most of the studies, realized in Western countries, have some warning about negative mpMRI:  Prostatitis and Benign Prostatic Hyperplasia (BPH) can mask PCa (12 ,33, 45);  Small tumors near the anterior horn can be missed at mpMRI (12, 35, 46);  PCa with predominant cribriform morphology is often invisible at imaging, and mucinous adenocarci-

Negative mpMRI: What’s next? What about the number of cores and the bioptic schemes? Update guidelines for the follow-up of patients with negative mpMRI

noma, although rarer, is also not readily visible on Diffusion Weighted Imaging (DWI), which is considered the “dominant sequence” by PIRADv2 (45, 46). Borofsky et al. reported that readers missed approximately 16% of lesions and underestimated the size of approximately 5% of csPCa in mpMRI. Approximately 58% of the missed cancers were PI-RADS 1-2; the remaining 42% were visible only in retrospect and were characterized as PI-RADS 3-4. Negative mpMRI resulted in underestimation of PCa size by at least 30% in 8% of pts with PCa (40). In this context, we purpose some practical solution: 1. Second readings of prostate mpMRI by subspecialist uro-radiologists can significantly improve NPV and predictive positive value (PPV); 2. Reported experience may reduce overcalling and avoid over targeting of lesions; 3. Greater education and training of radiologists in prostate mpMRI interpretation are advised. Many European countries are working to address this training need, in collaboration with European Society of UroRadiology (ESUR) and EAU; 4. The interpretation of a negative MRI-guided TPBx result is highly specific for each clinical scenario and it can be profoundly influenced by the prostate tissue characteristics, image acquisition, and TPBx technique (24).

GUIDELINES We consider the most important three studies regarding the role of mpMRI: the PROMIS Trial, the PRECISION Trial and the MRI-First Study (13, 47, 48). We also analyzed the last Cochrane review about PBx and mpMRI (49). The PROMIS trial assessed mpMRI, 12-core PBx and TPBx in 576 prospectively included biopsy-naïve men. Forty percent of patients had csPCa (defined as Gleason score ≥ 4 + 3 or cancer core length ≥ 6 mm) at TTR + PBx. mpMRI failed to report 7% Gleason 3 + 4 cancers with core lengths between 6 and 12 mm, but no Gleason 4 + 3 or worse cancers. When accepting missing this 7%, mpMRI (used as a triage test) could have avoided 27% of primary biopsies, while detecting 18% more csPCa and “missing” 5% of csPCa (13). Similar results were reported in the multi-center, randomized, non-inferiority PRECISION trial, in which 500 biopsy-naïve men were randomized to undergo either mpMRI with or without TBx, or standard Pbx (SPBx). Using mpMRI as a triage test could have avoided 28% of primary PBx, while detecting 12% more csPCa (defined as Gleason score ≥ 3 + 4) than SPBx and “missing” 13% of csPCa. These results were obtained in 25 centers (academic and non-academic) with mixed experience in both mpMRI and MR-targeted biopsy, and without restrictions on the use of a 1.5-T or a 3.0-T system, endorectal coil, or PBx technique (visual registration, software-assisted registration or in-bore) (47). The MRI-FIRST TRIAL was a prospective, multicenter, paired-diagnostic study conducted at 16 centers in France to address whether mpMRI before PBx would improve detection of csPCa in biopsy-naïve pts. All men underwent both PBx and hypoechoic-directed biopsies, followed by 2

cores of mpMRI ROI. A total of 253 pts were analyzed, with 21% with negative mpMRI. 75% of indolent cancer were identified by SPBx alone. The data of the study are consistent with prior studies and would suggest that maintaining SPBx will increase the risk of continued over diagnosis of indolent diseases while allowing a low, but consistent, rate of csPCa (48). In the Cochrane review the Authors reported that approximately one-third of all men had negative mpMRI and concluded that this kind of pts could be counselled to pursue clinical and biochemical monitoring as a reasonable alternative for SPBx, sharing decision making in current diagnostic work-up, as already recommended in international guidelines (49). All these studies, taken together, provide strong evidence regarding the benefit of pre-PBx mpMRI among men with no previous PBx, but leave questions regarding whether it is safe to avoid a PBx in men at risk for PCa with a low risk mpMRI (PI-RADS or Likert scale <2). Individual institutional experience with mpMRI and an active quality assurance program assessing mpMRI-targeted PBx outcomes is necessary to decide on the validity of this approach as a learning curve for both mpMRI and PBx has been shown. Moreover, the oncologic relevance of high-grade tumors missed on mpMRI are not yet entirely characterized. Additionally, the cost and feasibility of performing large volume mpMRIs must be considered. Cost-effectiveness studies appear to suggest the downstream benefit of PBx reduction or avoidance and increased quality adjusted life years through the adoption of an mpMRI and mpMRI-targeted PBx care pathway. Benefits and harms have to be balanced on an individual basis when considering re-PBx, with particular attention about factors such as comorbidities, family history with PCa (especially relatives), race, genitourinary history (e.g., prostatitis, sexually transmitted infection), PSA density, PSA velocity, and life expectancy. Panebianco et al. have recently suggested, after a negative mpMRI, for selected pts, a non-invasive follow-up based on confirmatory mpMRI and PSA measurements. Nevertheless, SPBx cannot be routinely omitted after negative mpMRI, especially in younger pts with strong clinical suspicion of PCa, due to the concrete possibility of missing csPCa, but mpMRI-silent (12). A reasonable and well-balanced proposal for follow-up could include the following statements (see also Figures 1, 2): PSA measurements: every 4 months during the first year, then every six months for the next four years, in the same laboratory test. mpMRI repeating: in case of PSA increasing > 25% over the previous value and then systematic PBx. Different PBx techniques: systematic vs targeted Systematic PBx: it is always necessary to consider the use of SPBx until the time that individual experience demonstrates a low risk of missed csPCa, even if this use of systematic PBx will increase the risk of over-detection. As a matter of fact, the importance of SPBx has been highlighted by a recent review written by the European Advances in Urological Diagnosis and Imaging - 2020; 3,1

C. Maccagnano, R. Hurle, E. Scapaticci, L. Nava, G. N. Conti, V. Scattoni. Figure 1. algorithm for biopsy naïve pts.

* of 25% PSA increasing comparing to the previous PSA

Figure 2. Elements to be considered in case of repeated PBx.

Association of Urology Young Academic Urologists Prostate Cancer Working Party (50). Additionally, PCa DR improves about 10 % using the combination of both targeted and SPBx as compared with a pure targeted strategy (51). Targeted PBx: There are three different kind of TPBx:  Cognitive-fusion PBx: operators mentally combine information from the mpMRI and TRUS to target lesions. These are highly dependent on the user with some studies showing inferiority to software-fusion TPBx (52).

Advances in Urological Diagnosis and Imaging - 2020; 3,1

 Software-fusion: software-based registration of mpMRI and TRUS. It has to be underlined that fusion systems tend to report a registration error between 1 and 3 mm, especially for region of interest (ROI) located anteriorly or towards the prostatic base, for whom Trans Perineal (TP)-PBx has to be preferred (51, 5356). Additionally, prostate deformation during MRI or TRUS (caused by placement of endorectal coil during mpMRI or TRUS probe during PBx, changes in patient position, or degree of bladder filling between imaging sessions) can lead to difficulties in accurately registering images (57-58). Moreover, sometimes PBx may be performed months after the MRI and cannot account for any glandular changes that occur in the interim (24).  In-bore MR-guided TPBx: PBx and mpMRI acquisition occur with the patient in the magnetic resonance (MR) scanner. Kaufmann et al. looked at csPCa DR of pts receiving this kind of PBx and they detected csPCa in 40% of patients compared to 23.7% with cognitive fusion; however, due to a small sample size, this was not statistically significant (52). Comparative studies suggest mpMRI-guided approaches are more accurate for PCa detection, but more method-specific distinctions among these approaches have yet to be made (59). Nevertheless, the PROFUS trial showed that at a center with considerable experience, fusion TPBx and cognitive fusion did not yield significantly different csPCa DR (20.3% vs. 15.1%, respectively), with cases of smaller lesions likely benefiting the most from fusion software (60). When compared to the standard-of-care 12-core systematic PBx, TPBx is useful in order to find greater rates of intermediate- and high-risk disease and lower rates of low-risk disease (24). In this context, Siddiqui et al. reported a sensitivity of 77% and a NPV of 70%, for detection of csPCa (61). However, sometimes the TPbx of a suspicious lesion seen on MRI is not confirmed to be csPCa, despite advances in imaging, PBx technique and urologist’s experience. Currently, there is no standard guideline for TPBx sampling

Negative mpMRI: What’s next? What about the number of cores and the bioptic schemes? Update guidelines for the follow-up of patients with negative mpMRI

of a lesion, which can range from a single biopsy core to a saturation biopsy. Previous studies have determined systematic saturation biopsies improve cancer detection versus 12-core systematic biopsies especially at low PSA values albeit with considerable morbidity (62, 63). Presumably, TPBx PCa DR would improve with additional cores obtained, but an optimal number of cores per lesion have yet to be established. With a learning curve for TPBx adoption, obtaining additional cores early on may improve accuracy until technique improves (64). The benefit of obtaining additional biopsy cores must be weighed against potential complications. In case of negative TPBx patient management relies on the identification of any sources of error to rule out missed disease. Other issues:  Considering the use of pre-PBx mpMRI, quality, experience of the interpreting radiologist, cost, are essential. Greater education and training of radiologists in prostate mpMRI interpretation are advised. Many European countries are working to address this training need, in collaboration with ESUR and EAU.  Availability of ancillary tests should be considered (Table 3).  Comorbidities, familiar history, life expectancy has to necessarily be considered. The proposal both for PBx-naïve and for pts with prior negative PBx are reported in Figures 1, 2 (65). USE OF NOMOGRAMS AND RISK CALCULATORS The use of nomograms and risk calculators can help with decision making, predict PBx results, predict pathological stage. It is important to explain the reliability, validity and limitations of any predictions made using these instruments.

CONCLUSIONS The data literature cannot allow to decide about a patient relying on mpMRI only. Quality control in the mpMRI pathway about mpMRI acquisition, mpMRI reading, and mpMRI-TPBx methods are needed, eventually with the help of experts in this field. Additionally, the ancillary tests can play a fundamental role in the decision-making process which has to be always shared with pts. Moreover, nomograms and risk calculators can help in this decisional process. The future perspective are about the role of biparametric MR, the clinical validity and utility of artificial intelligence with machine learning tools and the growing importance of the multidisciplinary approach.

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CORRESPONDENCE Carmen Maccagnano, MD, FEBU Department of Surgery, Division of Urology ASST Lariana, Nuovo Ospedale Sant’Anna Via Ravona, 20 -22042 San Fermo della Battaglia (CO) E-mail: carmen.maccagnano@gmail.com Phone: +39.31.585.9645

Advances in Urological Diagnosis and Imaging - 2020; 3,1

MINI

REVIEW

Which biopsy strategy should be recommended in men with a positive prostate MRI: Targeted sampling alone or combined with systematic biopsy? Gianluca Giannarini 1, Anwar R. Padhani 2. 1 2

Urology Unit, Academic Medical Centre “Santa Maria della Misericordia”, Udine, Italy; Paul Strickland Scanner Centre, Mount Vernon Cancer Centre, Northwood, UK.

Whether MRI-informed targeted biopsy combined with systematic biopsy is a superior strategy than targeted biopsy alone for detecting prostate cancer in men with a positive MRI remains debatable. In this mini-review, we examined original studies, the evidence from three recent systematic reviews with meta-analysis of randomized controlled trials, and agreement studies comparing the MRI-informed vs conventional systematic biopsy-based diagnostic pathways. Different biopsy strategies including targeted biopsy and/or systematic biopsy are evaluated focusing on diagnostic yields and biopsy avoidance. Data from the Cochrane diagnostic test accuracy systematic review showed that all MRI-informed targeted biopsy pathways have beneficial outcomes compared with conventional systematic biopsy, with potentially reduced risks and harms. MRI-informed targeted biopsy as the default strategy optimises diagnostic yields in men at first diagnosis and may be the only test required in a significant proportion. Deploying additional systematic biopsy depends on balancing risks and benefits according to clinical care priorities.

SUMMARY

KEY WORDS: Prostate neoplasms; prostate biopsy; magnetic resonance imaging.

The question as to whether MRI-informed targeted biopsy (TB) combined with systematic biopsy (SB) is a superior strategy than TB alone for detecting clinically significant prostate cancer (PCa) in men with a positive MRI remains unanswered. The highest levels of evidence are derived from sub-analyses of three recent systematic reviews with meta-analysis of randomized controlled trials (RCTs), and in agreement studies comparing the MRI-informed vs conventional SB-based diagnostic pathways (1-3). Only a single RCT has compared TB plus SB vs. TB alone (4) in men with positive MRI scans. Patients with previous negative SB and PSA level above 4 ng/ml were randomized to combined biopsy (software-assisted fusion TB plus SB) vs. in-bore TB only. The primary endpoint was the detection of any PCa. Unfortunately, the study was prematurely halted after an interim analysis had shown the pri-

Advances in Urological Diagnosis and Imaging - 2020; 3,1

mary endpoint would not be met. No difference was found in PCa detection rates between the two biopsy approaches and no meaningful comment can be made regarding the question of TB plus SB vs. TB alone given differences in technologies employed (transrectal ultrasound/MRI fusion vs in-bore MRI). In the absence of RCTs, we need to evaluate original studies and systematic re-views that address the question of the added value of SB to TB, and the added value of TB to SB (Figure 1). A subgroup analysis of the Cochrane Review (1) examined the add-ed value of SB to TB for PCa detection. Two definitions of clinically significant PCa (csP-Ca) were used, either Grade Group (GG) 2 or higher, or GG 3 or higher, PCa. Clinically insignificant (ciPCa) was defined as GG 1 PCa. Separate analyses were performed for biopsy-naïve men and men with previous negative biopsy, and for men with positive and negative MRI scan results. Table 1 shows the added value of SB for the detection of GG 2 or higher, and GG 3 or higher, PCa in biopsy-naïve men and in those previous negative biopsies. A total of 17 studies were included in the analysis of 2955 biopsy-naïve men in the Cochrane analysis. Per 100 biopsy-naïve men, TB only in men with positive MRI results detected approximately 39 men (39.2%, 95% confidence interval [CI] 33.3% to 45.7%) with GG 2 or higher PCa. When SB was added to TB, five additional men were detected (4.9%, 95% CI 2.8% to 8.3%). Therefore, the number needed to biopsy (NNB) for SB in addition to TB was 20 (95% CI 12 to 36) for detecting GG 2 or higher PCa, and 27 (95% CI 16 to 45) for detecting GG 3 or higher PCa. On the other hand, adding SB detected an extra 4.1% (95% CI 2.5% to 6.7%) GG 1 PCa, with an NNB of 24 (95% CI 15 to 40). A total of eight studies were included in the analysis of 920 men with previous negative biopsy. Per 100 men with a prior negative biopsy, TB only in men with positive MRI results detected approximately 29 men (28.6%, 95% CI 24.7% to 33.1%) with GG 2 or higher PCa. When SB was added to TB, three additional men were detected (2.7%, 95% CI 1.2% to 5.7%). Therefore, NNB for SB to detect

Which biopsy strategy should be recommended in men with a positive prostate MRI: Targeted sampling alone or combined with systematic biopsy?

There are three other pertinent studies that were not included in the previous analyses. Authors of a large retrospective study including 2103 men undergoing either initial or repeat biopsy (with or without a PCa diagnosis) and receiving both TB and SB, found that detection rate of GG 3 or higher was significantly higher with TB than with SB (20.2% vs. 13.9%, p<0.01) (8). Combined biopsy led to cancer diagnoses in 208 more men (9.9%) than with either method alone and to upgrading to a higher grade group in 458 men (21.8%). However, if only TB had been performed, 8.8% of GG 3 or higher PCa would have been misclassified. Interesting, among the 404 patients treated with radical prostatectomy, the rates of any upgrading or clinically significant upgrading on whole-mount histopathological analysis were substantially higher for SB (41.6% and 16.8%, respectively) and TB (30.9% and 8.7%, respectively) than for combined biopsy (14.4% and 3.5%, respectively). The authors concluded that combined biopsy improves diagnostic accuracy over either SB or TB alone and more accurately correlates the results of final histopathological analysis. In another retrospective two-centre study including 780 biopsy-naïve or previous negative biopsy patients (9), the individual patient probability of harbouring csPCa, defined as GG 2 or higher PCa outside the MRI index lesion, was estimated by building centre-specific risk calculators. For cohorts of both centres, omitting SB in patients with a calculated risk of <15% for the study outcome would have spared 16% of SB at the cost of missing 7% of csPCa. No net benefit was observed for lower threshold probabilities (<15%) of each calculator relative to the standard of care (performing SB in addition to TB to all patients), thus patients who might safely benefit from TB alone could not be identified. A prospective study including 152 men with previous negative biopsy as part of the FUTURE trial (10), which is a multicentre randomized controlled trial comparing three different methods of MRI-informed prostate biopsy for the detection of csPCa (GG2 or higher), showed that TB detected significantly more csPCa than SB (32% vs 16%; p<0.001, 95% CI 11% to 25%), but the additional value of SB was limited, because only 1.3% of csPCa would have been missed had SB been omitted. Of relevance, the combined use of TB plus SB has been recommended by the European Association of Urology (EAU) Guidelines on PCa since 2019 for biopsy-naïve men, but not for men with previous negative biopsy, in whom a TB only strategy is advised (11). The 2019 Prostate Imaging - Reporting and Data System Steering Committee guidance is concordant with the EAU Guidelines recommendations, leaving open the possibility of “focal saturation biopsy” as an option for some men (12). Focal saturation biopsy is a strategy that deploys several biopsy cores to target both the MRI-visible lesion and the “penumbra” surrounding it, although the optimal number of cores and their spatial distribution are still to be defined (13). A recent analysis of the data of the Cochrane diagnostic

Figure 1. Summary of added value of targeted to systematic biopsy, and systematic to targeted bi-opsy in biopsy-naïve men with a Grade Group 2 or higher prostate cancer prevalence of roughly 28%.

MRI=magnetic resonance imaging; SB = systematic biopsy; TB = targeted biopsy; GG = Grade Group

one additional man was 37 (95% CI 18 to 83) for detecting GG 2 or higher PCa, or 83 (95% CI 31 to 250) for detecting GG 3 or higher PCa. On the other hand, SB detected an extra 3% (95% CI 1% to 8%) GG 1 PCa, with an NNB of 33 (95% CI 13 to 100). In the systematic review with meta-analysis by Woo et al (2), only RCTs were included. Both TB only and TB plus SB were considered as interventions, while SB was considered as the comparator. A total of nine studies comprising either biopsy-naïve men or men with previous negative biopsy were selected. csPCa and ciPCa were defined as per individual studies. Men with positive and negative scans were not separately evaluated. As far as csPCa was concerned, there was a significant advantage of the intervention pathway versus the comparator with a detection ratio (DR) of 1.45 (95% CI 1.09 to 1.92, p=0.01), a subgroup analysis comparing TB vs. TB plus SB did not show significant difference in DR (1.82 [95% CI 1.11 to 2.98] for TB vs. 1.35 [95% CI 0.92 to 1.98] for TB plus SB, p=0.35). No subgroup analysis was performed for ciPCa as the outcome measure. In the systematic review with meta-analysis by Elwenspoek, et al. (3), seven studies of RCTs of biopsy-naïve men only were included. Similarly to Woo, et al. (2), both TB only and TB plus SB were considered as interventions, while SB was considered as the comparator. As with Woo, et al. (2) csPCa was defined as per individual studies. Both MRIinformed pathways were superior to SB in detecting csPCa. An indirect comparison of the two pathways was made considering only three studies. In two of them no additional cases of csPCa were detected combining TB plus SB (5, 6), while in the third one (7) an additional 10% of csPCa cases was found by adding SB to TB.

Advances in Urological Diagnosis and Imaging - 2020; 3,1

G. Giannarini, A. R. Padhani. Table 1. Added value of systematic to targeted biopsy including the numbers needed to biopsy to detect one additional clinically significant prostate cancer.

Population Biopsy-naïve

Previous negative biopsy

GG ≥2

MRI result

GG ≥3

Added value of SB (95% CI)

NNB (95% CI)

Added value of SB (95% CI)

NNB (95% CI)

Positive

4.9% (2.8-8.3%)

20 (12-36)

3.7% (2.2-6.1%)

27 (16-45)

Negative

8.1% (5.6-11.6%)

13 (9-18)

3.0% (1.6-5.5%)

33 (18-63)

Positive

2.7% (1.2-5.7%)

37 (18-83)

1.2% (0.4-3.2%)

83 (31-250)

Negative

5.3% (3.1-8.9%)

19 (11-32)

3.3% (1.7-6.3%)

31 (16-63)

MRI=magnetic resonance imaging; GG = Grade Group; SB = systematic biopsy; NNB = number needed to biopsy; CI = confidence interval

test accuracy systematic review (1) examined the utility of prostate MRI and MRI-informed TB for significant disease in men at first diagnosis (14). The paired agreement analysis data were reformulated for five unique biopsy strategies including TB and/or SB and focusing on diagnostic yields and biopsy avoidance. The authors found that all MRI-informed TB pathways have beneficial outcomes compared with conventional SB, with potentially reduced risks and harms. MRI-informed TB as the default strategy optimises diagnostic yields in men at first diagnosis and may be the only test required in a significant proportion. Deploying additional SB depends on balancing risks and benefits according to clinical care priorities. An in-depth analysis of clinical utility and cost-effectiveness of different diagnostic pathways for PCa is, however, beyond the scope of this mini-review. The authors of the present mini-review support the recommendations of the EAU Guidelines and Prostate Imaging - Reporting and Data System guidance. Data of this minireview will be used to update the current guidelines proposed by the Italian Prostate Biopsy Working Group (15).

7. Tonttila PP, Lantto J, Paakko E, et al. Prebiopsy multiparametric magnetic resonance imaging for prostate cancer diagnosis in biopsynaive men with suspected prostate cancer based on elevated prostate-specific antigen values: results from a randomized prospective blinded controlled trial. Eur Urol. 2016; 69(3):419-425. 8. Ahdoot M, Wilbur AR, Reese SE, et al. MRI-Targeted, Systematic, and Combined Biop-sy for Prostate Cancer Diagnosis. N Engl J Med. 2020; 382(10):917-928. 9. Dell’Oglio P, Stabile A, Soligo M, et al. There Is No Way to Avoid Systematic Prostate Biopsies in Addition to Multiparametric Magnetic Resonance Imaging Targeted Biopsies. Eur Urol Oncol. 2020; 3(1):112-118. 10. Exterkate L, Wegelin O, Barentsz JO, et al. Is There Still a Need for Repeated Systematic Biopsies in Patients with Previous Negative Biopsies in the Era of Magnetic Resonance Imaging-targeted Biopsies of the Prostate? Eur Urol Oncol. 2019 Jun 22. pii: S2588-9311(19)30080X. doi: 10.1016/j.euo.2019.06.005. [Epub ahead of print] 11. EAU – EANM – ESTRO – ESUR – SIOG – Guidelines on Prostate Cancer 2020. Available at https://uroweb.org/guideline/- prostate-cancer

REFERENCES

12. Padhani AR, Barentsz J, Villeirs G, et al. PI-RADS Steering Committee: The PI-RADS Multiparametric MRI and MRI-directed Biopsy Pathway. Radiology. 2019; 292(2):464-474.

1. Drost FH, Osses DF, Nieboer D, et al. Prostate MRI, with or without MRI-targeted biop-sy, and systematic biopsy for detecting prostate cancer. Cochrane Database Syst Rev. 2019; 4:CD012663.

13. Giannarini G, Crestani A, Rossanese M, et al. Multiparametric Magnetic Resonance Imaging-targeted Prostate Biopsy: A Plea for a Change in Terminology, and Beyond. S2588-9311(18)30211-6. doi: 10.1016/j.euo.2018.12.003. [Epub ahead of print]

2. Woo S, Suh CH, Eastham JA, et al. Comparison of Magnetic Resonance Imaging-stratified Clinical Pathways and Systematic Transrectal Ultrasound-guided Biopsy Path-way for the Detection of Clinically Significant Prostate Cancer: A Systematic Review and Metaanalysis of Randomized Controlled Trials. Eur Urol Oncol. 2019; 2(6):605-616. 3. Elwenspoek MMC, Sheppard AL, McInnes MDF, et al. Comparison of Multiparametric Magnetic Resonance Imaging and Targeted Biopsy With Systematic Biopsy Alone for the Diagnosis of Prostate Cancer: A Systematic Review and Meta-analysis. JAMA Netw Open. 2019; 2(8):e198427. 4. Arsov C, Rabenalt R, Blondin D, et al. Prospective randomized trial comparing mag-netic resonance imaging (MRI)-guided in-bore biopsy to MRI-ultrasound fusion and transrectal ultrasound-guided prostate biopsy in patients with prior negative biopsies. Eur Urol. 2015; 68(4):713-20. 5. Baco E, Rud E, Eri LM, et al. A randomized controlled trial to assess and compare the outcomes of two-core prostate biopsy guided by fused magnetic resonance and transrec-tal ultrasound images and traditional 12-core systematic biopsy. Eur Urol. 2016; 69(1):149-156.

6. Park BK, Park JW, Park SY, et al. Prospective evaluation of 3-T MRI performed before initial transrectal ultrasound-guided prostate biopsy in patients with high prostate-specific antigen and no previous biopsy. AJR Am J Roentgenol. 2011; 197(5):W876-W881.

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14. Schoots IG, Padhani AR, Rouvière O, et al. Analysis of Mag-netic Resonance Imaging-directed Biopsy Strategies for Changing the Paradigm of Pros-tate Cancer Diagnosis. Eur Urol Oncol. 2020; 3(1):32-41. 15. Fandella A, Scattoni V, Galosi A, et al. Italian Prostate Biopsies Group: 2016 Updated Guidelines Insights. Anticancer Res. 2017; 37(2):413-424.

CORRESPONDENCE Gianluca Giannarini, MD Urology Unit, Academic Medical Centre “Santa Maria della Misericordia” Piazzale Santa Maria della Misericordia 15 - 33100 Udine, Italy e-mail: gianluca.giannarini@hotmail.it - Twitter: @GGiannarini Phone: +390432552931 - Fax +390432552930

ORIGINAL

PAPER

Cognitive or visual biopsy role: Alone or a combination of techniques? Matteo Cevenini 1, Angelo Mottaran 1, Alessandro Bertaccini

1, 2,

Lorenzo Bianchi

1, 2,

Riccardo Schiavina

1, 2.

Department of Urology, University of Bologna, Bologna, Italy; Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Cardio-Nephro-Thoracic Sciences Doctorate, University of Bologna, Bologna, Italy. 2

SUMMARY

Aim: To perform a systematic review to evaluate the recent findings as to which technique of MRI-TB has the highest detection rate of Prostate cancer (cPCa) in both naive or with a prior negative biopsy patients. Methods: A Medline and Cochrane Central systematic review over the last 5 years up to 30 December 2019 was conducted. Search queries included: ‘guided biopsy’, ’cognitive biopsy’ or ‘Visual biopsy’. Four studies (level of evidence 2b, according to the Center for Evidence Based Medicine of Oxford) were included. Principal endpoint: evaluate which of the available techniques of transrectal biopsy should be preferred between Multiparametric Magnetic Resonace Imaging (mpMRI) fusion guided biopsy (FUS-GB), or without the software use: ‘cognitive or visual guided biopsy’ (COG-GB). Results and Conclusion: So far, it is not known which technique to prefer and there are no preferences in the guidelines or in literature. Meta-analysis of all the techniques demonstrated an advantage of a third technique, mpMRI-targeted biopsy with mpMRI-guidance (in-bore or MRI-GB) MRI-TB, compared with COG-TB only for overall PCa detection. Any of the analized studies showed a clear advantage of the three techniques for csPCa detection. In literature there is an evident lack of studies performing a comparison of the various techniques and supporting the real differences between them.

rates, when performed without prior imaging by Multiparametric Magnetic Resonance Imaging (mpMRI), are comparable between the two approaches (3); MpMRI is also used to investigate lesions suspicious for clinically significant prostate cancer (csPCa). In the urology practice, the evidence-based management of PCa, is currently led by clinical guidelines containing the best evidence available to the experts. European Association of Urology Guidelines (2020 release), for the first time, recommend, in case of prostatic biopsy, mpMRI guided, both in biopsy naive patients and in prior negative biopsy patients (4). In both cases, the council is given with a level of evidence 1A and a strong strength rating. A patient, suspected for csPCa, should undergo mpMRI-targeted biopsy; this technique can be performed or by US guidance, using a computer-based software due to identify and target the suspicious area shown on mpMRI onto the ultrasound: ‘fusion biopsy’ guided biopsy (FUS-GB) (Figure 1), or without the use of software: ‘cognitive or visual guided biopsy’ (COG-GB) (Figure 2). mpMRI-targeted biopsy can also be performed with mpMRI-guidance in the mpMRI scanner (in-bore or MRI-GB). No consensus, actually, exists regarding which of the three available techniques of transrectal biopsy (T3-TB) should be preferred.

KEY WORDS: :Prostate cancer, prostate biopsy, cognitive biopsy,

MATERIAL AND METHODS

visual biopsy, guided biopsy.

INTRODUCTION Prostate cancer (PCa) represents the second most common cause of cancer in men and it is usually suspected on the basis of digital rectal examination (DRE) and/or PSA level; the gold standard for PCa diagnosis is prostate biopsy (1, 2). So far, Ultrasound (US)-guided transrectal biopsy (TB) has been the standard of care, performed by either transrectal or transperineal approach. Cancer detection

We performed a Medline and Cochrane Central comprehensive systematic literature search up to 30 December 2019 within the last 5 years, in order to evaluate which technique of MRI-TB has the highest detection rate of cPCa in both naive or with a prior negative biopsy patients. Search queries included: ‘guided biopsy’, ’cognitive biopsy’ or ‘visual biopsy’. In this research all studies up to the level of evidence 2b, according to the Center for Evidence Based Medicine of Oxford (5) were included. Two independent reviewers extracted data. According to these criteria, 4 studies over Advances in Urological Diagnosis and Imaging - 2020; 3,1

M. Cevenini, A. Mottaran, A. Bertaccini, L. Bianchi, R. Schiavina. Figure 1. Fusion Biopsy: matching the Target lesion; pairing mpMRI and ultrasound images.

all were included. We analyzed a randomized clinical trial published by Hamid in 2018, whose aim was to compare the Visual-registration and Magnetic Resonance Imaging/Ultrasound (6). Image-fusion in detecting csPCa: a double blind prospective study by Simmons in 2018 (7) was also evaluated. This prospective trial goal was to evaluate the detection of csPCa using FUS GB compared to COG-GBTwo remnants studies, both performed by Wegelin, were evaluated. The former is a systematic review (2017) comparing T3TB (8); the latter is a multicenter randomized controlled trial, conducted between2014 and 2017 that, equally to the precedent review, had the purpose to evaluate PCa detection rate (DR) between the T3-TB (9).

RESULTS Hamid (6) performed a blinded, within-person randomized, paired validating clinical trial. 141 patients enrolled between 2014-2016 who had undergone a prior, both positive or negative TB and had a lesion on mpMRI, referred to a Likert score between 3â&#x20AC;&#x201C;5 (10), requiring targeted transperineal biopsy. Of them 129 patients underwent both COG-GB and FUS-GB: three samples for lesion for each procedure. 14 trained surgeons were involved and a different surgeon performed each of the biopsy strategies. Each method identified 13 cases, that the other missed. The combination of the two methods result-

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ed in a 14% (13/93 cases) improvement in csPCa DR. This difference was statistically significant (95% confidence interval: 7.6â&#x20AC;&#x201C;22.5). The PICTURE prospective trial (7) enrolled 249 consecutive patients from January 11, 2012 to January 29, 2014, in order to assess whether the use of FUS-GB alone is comparable to the use of systematic biopsies and cognitive targeted biopsies in stratifying patients into prostate cancer risk groups. As the primary study endpoint, clinically significant prostate cancer was defined as Gleason 4 + 3 or greater and/or any grade of cancer with a length of 6 mm or greater. Patients underwent mpMRI and were blinded to the results. Then transperineal template prostate mapping biopsies was performed. In 200 patients with a lesion, visual estimation and image fusion targeted biopsies were performed.Transperineal template prostate mapping biopsies detected 48.5% of PCa; mpMRI detected 40.5% PCa and csPCa was detected 17% of cases on transperineal template prostate mapping biopsy but not on FUS-TB but half was present in non-targeted areas. csPCa was found with COG-GB in 31.3% and in 28.4% with FUS-GP (McNemar test P = 0.5322). COG-GB missed 13.6% csPCa, detected by FUS-GB; furthermore FUS-GB missed 10.8% csPCa detected by COG.GB. In 2017 Wegelin performed a meta-analysis (8) of literature in order to compare the differences between MRI-GB, FUS-GB and COG-GB. The meta-analysis valued 43 studies with cohort size of patients ranging from 16 to1003 (median 106 patients). 21% of the studies performed MRI-GB

Cognitive or visual biopsy role: Alone or a combination of techniques? Figure 2. Cognitive or Visual Biopsy: no software needed to center the target lesion.

exclusively, while 79% combined it with TRUS-GB. Most studies applied a single technique of targeting, although 4 studies used both COG-GB and FUS-GB within the same population. Of the included studies that reported on the csPCa DR of both MRI-GB and TRUS-GB within the same population, three used COG-TB to perform targeting (n = 220), eight used FUS-TB (n = 2114), and two used MRITB (n = 163). The sensitivity for csPCa for COG-TB was 0.86 (95% CI: 0.69–0.94). The sensitivity for FUS-TB was 0.89 (95% CI: 0.82–0.93). The sensitivity for MRI-TB was 0.92 (95% CI: 0.76–0.98). No significant advantage of one technique on the other was recognized. It also seems that MRI-TB has an advantage over COG-TB in overall PCa detection (p = 0.02) whilst there is not a significant advantage of MRI-TB compared with FUS-TB, or FUS-TB compared with COG-TB for overall PCa detection. Only two studies, analyzed in this review, directly compare COG-TB and FUS-TB (11, 12). However none of them was able to demonstrate significant differences between these two techniques as far as csPCa and overall cancer detection rate, although a multivariate analysis in one of them (12) showed increased cancer detection rate in smaller MRI lesions. The most recent study, published by Wegelin in 2019 (9), is a multicenter randomized controlled trial. 665 patients with prior negative standard biopsy (SB) and a persistent suspicion of PCa were enrolled and underwent mpMRI. In case of lesion PIRADS ≥3 patients were randomized 1:1:1 for TB technique: FUS-TB, COG-TB, or inbore MRI TB. 234 (35%) patients had PIRADS≥3 lesions and underwent TB. No significant differences in overall PCa DR was found (FUS-TB 49%, COG-TB 44%, MRI-TB 55%, P= 0.4). There were no significant differences in the detection rates of csPCa (FUS-TB 34%, COG-TB 33%, MRI-TB 33%, P > 0.9). Differences in csPCa detection rates were 2% between

FUS-TB and MRI-TB (P= 0.8, 95% CI up 13% to 16%), 1% between FUS-TB and COG-TB (P > 0.9, 95% CI up14% to 16%), and 1% between COG-TB and MRI-TB (P > 0.9, 95% CI up14% to 16%).

DISCUSSION AND LIMITATIONS Hamid (6) found no statistically significant difference in overall DR of csPC. Each strategy identified 13 cases missed by the other: (86%) of these cancers. Even if only 129 patients underwent the procedure, the author tried to limit as much as possible the bias in a paired cohort design study and, as he supposed, a paired cohort design would allow confirmation of detection rate similarity between the two strategies. The key limitations were, olso, the lack of parallel-group randomisation and a limit on the number of targeted cores: three for each procedure, with a lower DR inside each single procedure. It has to be valued the impact on the data of the operator abilities. These data are related to experienced urologist, confirming that both the techniques are surgeon experience related. We also think that a possible suggestion to the second surgeon could be given at the ultrasound by the needle trace of the prior target biopsy. The same evaluation can be done towards the PICTURE prospective trial (7): there is a lack of uniformation and evaluation about the single operator expertise and there is not a procedure standardization. Moreover, these are a single center studies and multicenter trials would strengthen the external validity of these researchers. Wegelin meta-analysis (8) showed literature evident lack of lesions data and characteristics, such as PI-RADS classification, lesion size, and lesion location. Of 43 included studies only 5% presented data regarding lesion diameter, Advances in Urological Diagnosis and Imaging - 2020; 3,1

M. Cevenini, A. Mottaran, A. Bertaccini, L. Bianchi, R. Schiavina.

and 58% applied PI-RADS classification. In the present literature review, only two studies directly compared COGTB and FUS-TB (11, 12). However none of them was able to demonstrate significant differences between this two techniques, on csPCa and overall cancer detection rate, although a multivariate analysis showed increased cancer detection rate in smaller MRI lesions. The only advantage showed was overall PCa DR of MRI-TB compared with COG-TB. The 2019 Wegelin (9) multicenter randomized controlled trial confirmed what the previous meta-analysis shown: there is not a higher csPCa DR between the three techniques, but the author noted that despite the number of the enrolled patients (665), only 234 underwent prostate biopsy.

5. OCEBM Levels of Evidence: https://www.cebm.net/2016/05/ocebm-levels-of-evidence/

CONCLUSIONS

9. Wegelin O, van Melick HH, Hooft L, et al. The FUTURE Trial: A Multicenter Randomised Controlled Trial on Target Biopsy Techniques Based on Magnetic Resonance Imaging in the Diagnosis of Prostate Cancer in Patients with Prior Negative Biopsies. Eur Urol. 2019; 75: 582.

Target biopsy is the gold standard in the detection of prostate cancer (4). So far, it is not known which technique to prefer and there are no preferences, also, in the guidelines or in literature. Meta-analysis of all the three techniques demonstrated an advantage of MRI-TB compared with COG-TB for overall PCa detection. Any of the analised studies showed a clear advantage of the three techniques for csPCa detection. In literature there is an evident lack of studies performing a comparison of the various techniques and supporting the real differences between them. More multicenter randomised trials should be performed. Limited to current data, cognitive TB and image-fusion biopsy should be performed associating the two techniques together in order to achieve the highest detection rate for csPCa, reducing the single operator variability and increasing the numbers of samples in the target area (13). Moreover, data about diameter and site of the lesions and the number of the samples were found missing. Probably the diameter of the lesion affects the detection rate of the two methods and, to date, there is no cut-off to determine which of the two is more effective. Other important points to focus are also the standardization of the biopsy procedure and the surgeon and radiologist expertize, since inter-observer variability leads to different outcomes in PCa diagnosis.

6. Hamid S, Donaldson IA, Hu Y, et al. The SmartTarget Biopsy Trial: A Prospective, Within-person Randomised, Blinded Trial Comparing the Accuracy of Visual-registration and Magnetic Resonance Imaging/Ultrasound Image-fusion Targeted Biopsies for Prostate Cancer Risk Stratification. Eur Urol. 2019; 75:733. 7. Simmons LAM, Kanthabalan A, Arya M, et al. Accuracy of Transperineal Targeted Prostate Biopsies, Visual Estimation and Image Fusion in Men Needing Repeat Biopsy in the PICTURE Trial. J Urol. 2018; 200:1227. 8. Wegelin O, van Melick HHE, Hooft L, et al. Comparing Three Different Techniques for Magnetic Resonance Imaging-targeted Prostate Biopsies: A Systematic Review of In-bore versus Magnetic Resonance Imaging-transrectal Ultrasound fusion versus Cognitive Registration. Is There a Preferred Technique? Eur Urol. 2017; 71:51.

10. Rosenkrantz AB, Lim RP, Haghighi M, et al. Comparison of interreader reproducibility of the prostate imaging reporting and data system and Likert scales for evaluation of multiparametric prostate MRI. AJR Am J Roentgenol. 2013; 201: W612-8. 11. Puech P, Rouviere O, Renard-Penna R, et al. Prostate cancer diagnosis: Multiparametric MR-targeted biopsy with cognitive and transrectal US-MR fusion guidance versus systematic biopsy - prospective multicentre study. Radiology. 2013; 268:461-9. 12. Wysock JS, Rosenkrantz AB, Huang WC, et al. A prospective, blinded comparison of magnetic resonance (MR) imaging-ultrasound fusion and visual estimation in the performance of MRtargeted prostate biopsy: The PROFUS trial. Eur Urol. 2014; 66: 343-51. 13. Galosi AB, Maselli G, Sbrollini G, et Al Cognitive zonal fusion biopsy of the prostate: Original technique between target and saturation. Arch Ital Urol Androl. 2016; 88(4):292-295.

REFERENCES 1. Fandella A, Scattoni V, Galosi AB, et al. Italian Prostate Biopsies Group: 2016 Updated Guidelines Insights. Anticancer Res. 2017; 37(2):413-424. Review. 2. Prostate Cancer - Cancer Stat Facts National Cancer Institute â&#x20AC;&#x201C; surveillance, epidemiology, and end results program https://seer.cancer.gov/statfacts/html/prost.html (2018), Accessed 6th Mar 2018. 3. Xue J, Qin Z, Cai H, et al. Comparison between transrectal and transperineal prostate biopsy for detection of prostate cancer: a meta-analysis and trial sequential analysis. Oncotarget. 2017; 8: 23322. 4. Mottet N, Cornford P, Van den Bergh RCN, et al. EAU Guidelines: Prostate Cancer 2020. https://uroweb.org/guideline/prostate-cancer/#5

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CORRESPONDENCE Matteo Cevenini Department of Urology, University of Bologna, Bologna, Italy. E-mail: matteoceve@gmail.com

ORIGINAL

PAPER

Cost-effectiveness of the MRI-based approach in naive patient and rebiopsy patient

Angelo Mottaran ¹, Matteo Cevenini ¹, Lorenzo Bianchi ¹, ², Riccardo Schiavina ¹, ² Alessandro Bertaccini ¹, ². 1 2

Objective. The aim of our work is to establish if the mpMRI (multiparametric magnetic resonance imaging) target biopsy pathway is cost effective in the Italian Healthcare System. Material and Methods. We included the main studies published in the last 3 years evaluating the cost-effective of the MRI in countries with different health systems. Results. Faria et al. and Brown et al. compared diagnostic strategies of combinations of mpMRI, TRUSB (trans-rectal ultrasound biopsy), and TPMB. They obtained 383 different strategies. In the most cost effective substrategy (M7) all men received mpMRI and men with a suspicion of clinically significant (CS) cancer received an MRI-targeted TRUSB. Men in whom MRI-targeted TRUSB did not detect CS cancer received a second MRI-targeted TRUSB. In Barnett et al patients underwent MRI followed by target fusion or combined biopsy on positive MRI and standard or no biopsy on negative MRI, using Prostate Imaging Report And Data System score to decide to make biopsy or not. The most efficient strategy was the use of MRI followed by combined biopsy if MRI was positive and no biopsy if MRI was negative. Discussion. Considering the National Health Sistem (UK) reference costs, the most cost-effective strategy is the substrategy M7. However the results of the short term model on the costs and outcomes of testing must be combined with the results of the long-term model on the costs and outcomes of radical treatment and observation. Conclusions. mpMRI is cost effective as the first test for the diagnosis of prostate cancer, when followed by an MRI-targeted TRUSB in men in whom the MPMRI suggests a suspicion for CS cancer, and a second systematic biopsy if no CS cancer is found at the first biopsy.

SUMMARY

KEY WORDS: Prostate cancer, magnetic resonance imaging, prostate biopsy, MRI-fusion biopsy, cost-effectiveness analysis.

INTRODUCTION Prostate cancer (PCa) is the most common cancer in men and the sixth leading cause of cancer death among men worldwide. Men with high PSA usually undergo systematic biopsy with the result of morbidity derived from the procedure (fever, infection, sepsis, ...) many unnecessary biopsies, the detection of many clinically insignificant cancers and sometimes clinically significant cancers are missed. A pathway with a triage imaging test to decide which men with elevated PSA should go to biopsy might both reduce unnecessary biopsy, sequelae and in improve diagnostic accuracy.The aim of our work is to establish if the magnetic resonance imaging (MRI) target biopsy pathway is cost effective both in naive and re-biopsy patients.

MATERIAL AND METHODS Unfortunately, there are no cost effectiveness studies related to the Italian scenario and all articles in literature refer to other countries’ health systems. Besides the costeffectiveness of the diagnostic strategies depends not only on their short-term outcomes but also on the long term outcomes (lifetime costs, survival, quality adjusted survival) of the subsequent management decisions. It’s clear that the long term clinical effectiveness and cost-effectiveness of treatments will determine the real value of the diagnostic strategies. No study was identified that reported the lifetime costs and quality adjusted survival of men with prostate cancer managed with primary care, active surveillance and radical treatments. We included the main cost-effectiveness studies published in the last 3 years on Pubmed, cited in the Cochrane review published in 2018 (1), evaluating the cost-effective Advances in Urological Diagnosis and Imaging - 2020; 3,1

A. Mottaran, M. Cevenini, L. Bianchi, R. Schiavina, A. Bertaccini.

of the MRI in countries with different health systems. We analyzed the two studies published by Venderink in 2017 (6) and Barnett in 2018 (5) respectively related to the Dutch and American data. The most important cost analysis studies by Faria, et al. and Brown, et al. have been published in 2018 and are based on the Prostate MR Imaging Study (PROMIS, 2017) (4). These studies seem to be the most important in our analysis considering that the Italian health system is very similar to the British one.

RESULTS - Faria, et al. (2018) (2) compared diagnostic strategies of clinical combinations of mpMRI, trans-rectal ultrasound biopsy (TRUSB), and template prostate mapping biopsy (TPMB), in addition to the use of TRUSB and TPMB in isolation. These included strategies using mpMRI to decide whether a TRUS biopsy or TPM biopsy is necessary and target the TRUSB, and strategies starting with TRUSB and using mpMRI to decide whether to repeat a biopsy. The model had a diagnosis and a long-term component: for the first component a decision tree combined the information on diagnostic accuracy of the tests to determine the accuracy of the test combinations and for the long term outcomes they used a cohort Markov, with two health states for men with no cancer (alive and dead) and three states for men with cancer: localized cancer, metastatic cancer, and death. The main outcomes were cost effectiveness of diagnosis, defined as the strategies that detect the most clinically significant (CS) cancers for a given pound spent in testing, and long-term cost effectiveness, defined as the strategies that achieve the most health outcomes given their costs, for alternative costeffectiveness thresholds. The results are probabilistic in that they are the average of over 1000 Monte Carlo simulations. They found 14 strategies that reached at least 80% of CS PCa. In particular in M7 substrategy, all men receive mpMRI and men with a suspicion of CS cancer receive an MRI-targeted TRUSB. Men in whom MRI-targeted TRUSB did not detect CS cancer receive a second MRI-targeted TRUSB. M7 222 detects 95% (95%CI92% to 0.98%) and costs £807 (95%CI £777 to £833). This mpMRI definition and cut-off refer to MRI-targeted TRUSB in 96% of men: all men with high-risk CS cancer, 98% with intermediate-risk CS cancer, 92% with low-risk non-CS cancer. T7 consisted of testing all men with TRUSB, followed by mpMRI in men in whom CS cancer was not detected, and a repeat MRI-targeted TRUSB in men with negative TRUSB if there is a suspicion of CS cancer at the MPMRI. T7 223 detects 91% (95% CI 86–94%) CS cancers and costs £709 (95% CI £688–730). P4 2 consists of TRUSB for all men and TPMB for those in whom TRUSB did not detect CS cancer. It has perfect sensitivity but costs £1332 (95% CI £1278–1385). The strategy attaining the greatest expected health outcomes was P4 2, and the next best strategy is M7 222. The ICER of P4 2 versus M7 222 was £30 084/QALY. Next best to M7 222 is T7 223, and the ICER of M7 222 versus T7 223 is £7076/QALY gained, making it a cost-effective strategy in the UK setting.

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- In 2018 Brown, et al. (3) compared the diagnostic outcomes, short term costs and health outcomes (as HRQoL) of different strategies obtained by the combination of mpMRI imaging, TRUS guided biopsy (current standard) and TPM biopsy with the same model seen in Faria, et al. (2). The authors obtained 32 different combinations to diagnose prostate cancer. These combinations have been evaluated for different diagnostic definitions and cut off point forming 383 sub strategies with a short term cost between 244£ and 1654£ per man to the UK NHS. As in the cited study by Faria et al the most cost-effective strategy involved testing all men with mpMRI, followed by MRI-guided TRUS-guided biopsy in those patients with suspected CS cancer, followed by re-biopsy if CS cancer was not detected. This strategy is cost-effective at the TRUS-guided biopsy definition 2 (any Gleason pattern of ≥4 and/or cancer core length of ≥4mm), mpMRI definition 2 (lesion volume of ≥0.2ml and/or Gleason score of ≥ 3 + 4) and cut-off point 2 (likely to be benign) and detects 95% (95% CI 92% to 98%) of CS cancers. - Barnett, et al. (5) used a validated Markov model of prostate cancer onset and progression with 5 pretreatment states. Patients from ages 55 to 69, with PSA >4 ng/ml underwent MRI followed by target fusion or combined biopsy on positive MRI and standard or no biopsy on negative MRI, using PIRADS (Prostate Imaging Report and Data Systems) score equal or superior to 3 to decide to make biopsy or not. Deaths averted, quality-adjusted life-years (QALYs), cost and incremental cost-effectiveness ratio (ICER) were estimated for each strategy. Based on this study, MRI to screen men for PCa is cost-effective assuming a willingness-to-pay threshold of 100,000 $/QALY threshold. The most efficient strategy was the use of MRI followed by combined biopsy if MRI was positive and no biopsy if MRI was negative. The strategies that performed a standard biopsy on negative MRI (PIRADS<3) were more expensive and less effective than strategies that performed no biopsy on negative MRI. This is the best screening strategy and cost effective with an ICER of $23483/QALY. Threshold analysis suggest MRI continues to be cost-effective when the sensitivity and specificity of MRI and combined biopsy are simultaneously reduced by 19% points. - Venderink, et al. (6) in their decision analytic Markov model compared the cost effectiveness of two new diagnostic pathway with the current standard for detecting CS PCa (TRUS guided biopsy in patients with suspected CSPCa). In the first pathway an elevated PSA o abnormal digital rectal exploration was followed by mpMRI and in case of suspicious lesion a MRI-TRUS-fusion biopsy was performed. In the second pathway they replaced the MRITRUS-fusion biopsy with in-bore-MRI guided biopsy. A Markov model was used to represent follow up after different health states (prostatectomy, radiotherapy, active surveillance, death). Effectiveness was measured as health-related quality of life in quality-adjusted life years (QALY). They used willingness-to-pay threshold of 80,000 euro as recommended by the Dutch Council for Public Health and Care. A base case analysis was performed to compare systematic trans rectal ultrasound and image fusion-guided biopsies. Because of a

Cost-effectiveness of the MRI-based approach in naive patient and rebiopsy patient

lack of appropriate literature regarding the accuracy of direct in-bore MRI guided biopsy a threshold analysis was performed. According to the model MRI-TRUS fusion is more effective than TRUS alone, with an ICER for MRITRUS fusion guided biopsy of 1386 euro per QALY gained. Direct in-bore MRI guided biopsy would be cost effective if the sensitivity for clinically significant prostate cancer of MRI guided biopsy were 11.8% higher than the sensitivity of MRI-TRUS fusion. If mpMRI findings are abnormal in a patient with clinically significant prostate cancer, MRI guided biopsy has to be true-significant in at least 88.8% of cases, with an ICER of 80,000 euro per QUALY gained.

DISCUSSION AND LIMITATIONS As seen in Faria, et al. (2) and Brown, et al. (3) the combinations, definitions and cut-off points form 383 diagnostic sub strategies which detected from 15% to 100% of PCa with a cost ranging from 244£ to 1653£. A diagnostic strategy consisting of mpMRI first and up to two MRI-targeted TRUSB is more likely to be cost effective at costeffectiveness thresholds at and below £30 000. The most clinically effective strategy is testing all men with TRUSB, mpMRI and cut-off at definition 2 and retesting men in whom CS cancer was not detected with TPMB. However in order to asses a real cost effective-strategy, the results of the short term model on the costs and outcomes of testing must be combined with the results of the long-term model on the costs and outcomes of radical treatment and observation. Obviously the quality adjusted life expectancy and health-care costs of men diagnosed with prostate cancer depend on the severity of their cancer and the consequent treatment. Considering the NHS reference costs, the cost-effective strategy at the health opportunity costs of 13,000£ 20,000£ and 30,000£ per QALY gained is the substrategy M7 222 that achieves 8.72 discounted QALY (95% CI 8.4 to 9.04) and costs £5367 (95% CI 92% to 98%). These two studies have been the first to examine the cost-effectiveness of all possible combinations of mpRMN, TRUS-guided biopsy and TPM-biopsy to diagnose prostate cancer and distinguish between non-CS and CS cancers. The access to data from PROMIS, the largest clinical study on mpRMN and TRUSB, facilitated the comparison with the different combinations of tests, definitions, and cut off points. However even these important studies have limitations and areas of uncertainty: 1) The recent guidelines based on the Prostate Imaging Reporting and Data System suggests that men with PIRADS 1 or 2 should not be biopsied in order to avoid diagnosis. This may not be equivalent to the cut-off reported here, considering that the PROMIS study did not use PI-RADS at the contrary of the study by Barnet, et al. 2) A limitation of PROMIS and of these two studies based on its data is that it did not include the combination of additional clinical and genetic characteristics for diagnosis and risk stratification. 3) The sensitivity of MPMRI and TRUSB depends on their

definitions and cut-offs. So the sensitivity of the first and second MRI-targeted TRUSBs are key cost-effectiveness drivers. 4) Testing all men with TRUS biopsy and retesting men in whom CS cancer was not detected with TPMB is not cost effective at current cost-effectiveness thresholds and will not be clinically feasible to deliver across the board in any healthcare setting. These findings can be generalized to countries with similar population, outcomes, pricing and Beveridge’s health care system. 5) The cost-effectiveness of less sensitive diagnostic strategies is favored if the long term outcomes of men who are incorrectly classified with no cancer were overestimated. It’s clear that the base case may be biased towards M7 222 and against P4 2 or P1 which detected all cancers. Management of men classified as having no cancer or non-CS cancer also has an impact on the scope for investment in diagnosis. More sensitive monitoring protocols improve the cost effectiveness of less sensitive and less costly diagnostic strategies. There is a dearth of evidence on the effectiveness of repeated testing protocols, which constitutes an important limitation of the current evidence base in support of policy, and meant that these analyses could not formally evaluate the use of such protocols. 6) In order to evaluate the cost effectiveness of diagnostic tests, evidence is required on the long-term outcomes of patients who are correctly diagnosed and those who are misclassified, given their true disease status. The existing studies used TRUS biopsy to diagnose and risk stratify patients and some individuals may have been under-diagnosed. As a consequence, their long-term quality-adjusted survival may have been overestimated, and the cost effectiveness of treatment may have been under-estimated. This issue can only be resolved with better-quality evidence on the outcomes of men with prostate cancer. Even the studies by Barnett et al and Venrink et al al demonstrated that MRI followed by targeted fusion-guided biopsy seems to be a cost effective approach to the early detection of PCa when compared with systematic transrectal ultrasound guided biopsy in Dutch and American scenario.

CONCLUSIONS The most recent studies revealed that mpMRI is cost effective as the first test for the diagnosis of prostate cancer, when followed by an MRI-targeted TRUSB in men in whom the MPMRI suggests a suspicion for CS cancer, and a second systematic biopsy if no CS cancer is found at the first biopsy. These findings are sensitive to sensitivity of MRI-targeted TRUS biopsy, and long-term outcomes of men with cancer. Finally, the application in clinical practice of a wide use of magnetic resonance imaging must be considered in relation to the availability of dedicated radiologists, an adequate number of equipment and waiting times congruous to the diagnosis of prostate cancer. Advances in Urological Diagnosis and Imaging - 2020; 3,1

A. Mottaran, M. Cevenini, L. Bianchi, R. Schiavina, A. Bertaccini.

REFERENCES

prostate biopsy alone: the PROMIS study. Health Technol Assess. 2018; 22(39):1-176.

1. Drost FH, et al. Prostate MRI, with or without MRI-targeted biopsy, and systematic biopsy for detecting prostate cancer. Cochrane Database Syst Rev. 2019; 4:CD012663.

4. Ahmed HU. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet. 2017; 389(10071):815-822.

2. Faria R, et al. Optimising the Diagnosis of Prostate Cancer in the Era of Multiparametric Magnetic Resonance Imaging: A Cost-effectiveness Analysis Based on the Prostate MR Imaging Study (PROMIS). Eur Urol. 2018; 73(1):23-30.

5. Barnett CL, et al. Cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer. BJU Int. 2018; 122(1):50-58.

3. Brown LC. Multiparametric MRI to improve detection of prostate cancer compared with transrectal ultrasound-guided prostate biopsy alone: the PROMIS study. Multiparametric MRI to improve detection of prostate cancer compared with transrectal ultrasound-guided

6. Venderink, et al. Cost-Effectiveness Comparison of Imaging-Guided Prostate Biopsy Techniques: Systematic Transrectal Ultrasound, Direct In-Bore MRI, and Image Fusion AJR Am J Roentgenol. 2017; 208(5):1058-1063.

CORRESPONDENCE Angelo Mottaran Department of Urology, University of Bologna, Bologna, Italy E-mail: angelo.mottaran@gmail.com

Advances in Urological Diagnosis and Imaging - 2020; 3,1

ORIGINAL

PAPER

Prostate biopsy and risk of sepsis: Which antibiotic prophylaxis? Pietro Pepe 1, Andrea Fandella 2. 1 2

Urology Unit - Cannizzaro Hospital, Catania, Italy; Department of Urology, Giovanni XXIII Clinic, Monastier di Treviso, Treviso, Italy.

Introduction. The incidence of sepsis performing systematic prostate biopsy and/or targeted approach has been evaluated. Materials and methods. The data presented are based on a narrative review. Search in PubMed and Medline was performed with a focus on randomised controlled trials and metaanalyses. A systematic review and metanalysis of available to date studies about the risk of sepsis in patients who underwent prostate biopsy has been performed until October 2019. Primary outcome was infectious complications. Results. Among the 87 papers published beetween January 2017 to October 2019 only 33 publications were idientified as elegible for the study: 5 systematic revision of the literature, 5 meta-analyses/randomised prospective studies and 23 clinical trials. The use of targeted antibiotic therapy combined with rectal preparation with povidone-iodine decrease the risk od infections and/or sepsis in men submitted to transrectal biopsy; on the other hand, the transperineal approach reset the risk of sepsis. Conclusions. Men candidate to transrectal prostate biopsy (especially those at risk for sepsis) should perform rectal preparation with povidone-iodine and rectal swab culture combined with targeted antibiotic prophylaxis to reduce the risk od infections. The transperineal prostate biopsy approach reset the risk of sepsis also when an higher number of needle cores is performed; On the contrary, a greater number of needle cores during transrectal biopsy is significantly correlated with the risk of urinary infection and/or sepsis also in the patients submitted to targeted antibiotic therapy.

SUMMARY

KEY WORDS: Prostate cancer; prostate biopsy complications; prostate biopsy and sepsis.

INTRODUCTION Prostate cancer (PCa) is the most frequent tumor diagnosed in elder men; in the last decade a greater rate of prostate biopsy complications has been reported secondary to increased number of needle cores, use of antiplatelet agents and infections. However patients may

offered mechanical bowel preparation and receive prophylactic antibiotics, standards of care have not been established with an increased incidence of infections and bacterial resistance to antibiotics. Although less than 50% of the papers referring to prostate biopsy reports adverse events following the procedure, serious complications incidence requiring hospital admission ranges from 0.1% to 2.5% in the most of the cases secondary to urinary tract infection (UTI), fever or sepsis. In this study the incidence of sepsis performing transrectal or transperineale systematic and/or targeted approach has been evaluated.

MATERIALS AND

METHODS

The data presented are based on a narrative review. Search in PubMed and Medline was performed with a focus on randomised controlled trials and meta-analyses. A systematic review and metanalysis of available to date studies about the risk of sepsis in patients who underwent prostate biopsy has been performed until October 2019. Primary outcome was infectious complications.

RESULTS Among the 87 papers published beetween January 2017 to October 2019 only 33 publications were idientified as elegible for the study: 5 systematic revision of the literature (1,2,15-17), 5 meta-analyses/randomised prospective studies (11,18,24,26,31) and 23 clinical trials (3,4,5-14,1923,25,27-33). The 33 studies were performed by multicenter departments of different Countries in 7 cases; in USA in 7 cases; in Australia in 3 cases; in Koera, Egypt, Brazil, Japan, Belgium and Canada in 1 case; in Italy 10 cases.

DISCUSSION Clinical complications and hospital admissions following transrectal prostate biopsy have increased during the last Advances in Urological Diagnosis and Imaging - 2020; 3,1

P. Pepe, A. Fandella.

10 years primarily due to an increasing rate of infections. In a population based study of 75,190 men who underwent transrectal prostate biopsy an increased 30-day hospital admission rate from 1.0% in 1996 to 4.1% in 2005 has been reported; in detail, the majority of hospital admission were infections (71.6%), followed by blending (19.4%) and urinary retention (9.0%). In 10,474 transrectal biopsies performed in the European Randomized Study of Screening for Prostate Cancer (Rotterdam section) fever and hospital admission was registered in the 4.2% and 0.8% of the cases, respectively. In 5,798 men submitted to transrectal prostate biopsy has been demonstrated an increased incidence of infections from 0.52% in 2002-09 to 2.15% in 2010-11 secondary in the 52% of the cases to pathogens (Escherichia Coli in the 75% of the cases) resistant to ciprofloxacin especially in patients with diabetes, chronic obstructive pulmonary disease and in those hospitalized during the precedent month. Recently, in a random sample of Medicare partecipants in SEER (Surveillance, Epidemiology and End Results) regions from 1991 to 2007 prostate biopsy was associated with a 2.65fold increased risk of hospitalization secondary to infections within 30 days compared to the control population. Although antibiotic prophylaxis following transrectal prostate biopsy (5) is mandatory there are no definitive data to confirm that antibiotics for long-course (3 days) are superior to short-course treatments (1 day), moreover considering the increased risk of infections new strategies have been proposed to reduce UTI, prostatitis and bacteremia. In the last years, the rectal cultures obtained before transrectal biopsy to facilitate targeted antibiotic prophylaxis (15) and decrease the overall cost of care (16) has been suggested. In this light, transperineal prostate biopsy has been recommended to reduce number of infections and sepsis rate; Miller et al. (32) compared side effects following transrectal (116 cases) and transperineal (75 cases) biopsy showing a superimposable incidence of clinical complications (19.8 vs 22.2%) but a sepsis rate equal to 1.2 vs 0%, respectively. In definitive, transperineal biopsy compared to transrectal approach allows to reset risk of sepsis that is continuously increasing because antibiotics resistant flora (i.e., Escherichia Coli infection). Finally, in a systematic revision of the literature on 6,609 patients submitted to transperineal biopsy the risk of sepsis was equal to 0-0.07% (4, 16).

DOES MRI/TRUS

TARGETED BIOPSY REDUCE THE COMPLICATIONS RATE OF PROSTATE BIOPSY?

The transperineal approach performing systematic or targeted biopsy reset the risk of sepsis; in addition, a greater number of transperineal needle cores does not increase the risk of sepsis (1-4). A greater number of needle cores performed by transrectal biopsy is significantly correlated with the risk of urinary infection and/or sepsis also in the patients submitted to targeted antibiotic therapy obtained from rectal swab culture (5, 6). At the same time, other Authors have not reported that the risk of infection/sepsis in men submitted to transrectal biopsy is correlated to the number of needle cores (1, 7).

Advances in Urological Diagnosis and Imaging - 2020; 3,1

WHAT

SHOULD BE DO IN DAILY CLINICAL PRATICE TO REDUCE THE RISK OF SEPSIS? WHICH ANTIBIOTIC PROPHYLAXIS?

The recommendations previously formulated by the Italian Prostate Biopsies Group (33) are still suggested (1-33) to reduce the risk of infections/sepsis in men who underwent transrectal prostate biopsy (Table 1): 1) rectal preparation with povidone-iodine (8); moreover, rectal swab culture prior to transrectal prostate biopsy can help use targeted prophylactic antibiotics (1, 2, 5, 8, 10); 2) The transperineal prostate biopsy approach reset the risk of sepsis (3, 4, 11-18). The administration of antibiotic targeted therapy obtained by rectal swab culture dose not reset the risk of sepsis (0.64% out 15.236 submitted to transrectal prostate biopsy); in addition, the use of multidrug and/or targeted antibiotic prophilaxis reduce the risk of sepsis in comparision wih the use of a single and aspecific antibiotic prophylaxis (19). The detection of resistant bacterials strains to quinolone antibiotics increase the risk of hospidalizations expecially in men enrolled in Active Surveillance protocols (20). The transperineal prostate biopsy approach decrease significantly the risk of sepsis (0-0.07% of the cases) (3, 4, 12, 14-16).

Table 1. Patients candidate to transrectal prostate biopsy at risk for sepsis. Chronic and relapsing prostatitis Bowel recurrent infections Repeated antibiotic therapy Prostatitis following prostate biopsy Recent hospitalization Active Surveillance Chronic bowel infections Immunodepression

The use of targeted antibiotic therapy combined with rectal preparation with povidone-iodine decrease the risk od infections and/or sepsis in men submitted to transrectal biopsy (21, 22); the antibiotic prophylaxis should be obtained performing the rectal swab colture (expecially in men at risk for sepsis) and should administered for a maximum of three days (18). The use of fosfomycin is suggested in men with proven quinolone antibiotic resistance. (23, 24); at the same time, fosfomycin showed less efficacy in the presence of Klebsiella (25). A single dose of intravenous administration of amynoglicoside (26) or ceftriaxone (27) could be used instead of rectal swab culture. Finally, in men candidate to transperineal prostate biopsy a single dose of antibiotic (i.e., cafazolin) (18, 30) could be sufficient for the antibacterial prophylaxis (Table 2).

Prostate biopsy and risk of sepsis Table 2. Recommendations in men candidate to transrectal prostate biopsy at risk for sepsis suggested by Italian Prostate Biopsies Group. Level of Evidence (L.E.) and Grade of Recommendation

CONCLUSIONS Men candidate to transrecatl prostate biopsy (especially those at risk for sepsis) should perform before the procedure rectal preparation with povidone-iodine and rectal swab culture combined with targeted antibiotic prophylaxis to decrease the risk od infections. On the contrary, the transperineal prostate biopsy approach reset the risk of sepsis also when an higher number of needle cores is performed. On the contrary, a greater number of needle cores performed by transrectal biopsy is significantly correlated with the risk of urinary infection and/or sepsis also in the patients submitted to targeted antibiotic therapy obtained from rectal swab.

REFERENCES

8. Roberts MJ, Bennet HY, Harris PN, et al. Prostate Biopsy-related infection: a Systematic review of risk factors, prevention strategies, and management approaches. Urology. 2017; 104:11-21. 9. Ryu JW, Jung SI, Ahn JH, et al. Povidone-iodine rectal cleansing and targeted antimicrobial prophylaxis using rectal swab cultures in men undergoing transrectal ultrasound-guided prostate biopsy are associated with reduced incidence of postoperative infectious complications. Int Urol Nephrol. 2016; 48:1763-1770. 10. Boeri L, Fontana M, Gallioli A, et al. Rectal Culture-Guided Targeted Antimicrobial Prophylaxis Reduces the Incidence of PostOperative Infectious Complications in Men at High Risk for Infections Submitted to Transrectal Ultrasound Prostate Biopsy - Results of a Cross-Sectional Study. PLoS One. 2017; 12(1):e0170319. 11. Xiang J,Yan H, Li J, Wang X, et al. Transperineal versus transrectal prostate biopsy in the diagnosis of prostate cancer: a systematic review and meta-analysis. World J Surg Oncol. 2019; 17:31.

1. Pilatz A, Veeratterapillay R, Kรถves B, et al. Update on Strategies to Reduce Infectious Complications After Prostate Biopsy. Eur Urol Focus. 2019; 5(1):20-28.

12. Pepe P, Garufi A, Priolo GD, et al. Is it Time to Perform Only Magnetic Resonance Imaging Targeted Cores? Our Experience with 1,032 Men Who Underwent Prostate Biopsy. J Urol. 2018; 200:774778.

2. Borghesi M, Ahmed H, Nam R, et al. Complications After Systematic, Random, and Image-guided Prostate Biopsy. Eur Urol. 2017; 7:353-365.

13. Pepe P, Garufi A, Priolo GD, Pennisi M. Multiparametric MRI/TRUS Fusion Prostate Biopsy: Advantages of a Transperineal Approach. Anticancer Res. 2017; 37:3291-3294.

3. Pepe P, Aragona F. Prostate biopsy: results and advantages of the transperineal approach--twenty-year experience of a single center. World J Urol. 2014; 32:373-77.

14. Pepe P, Pennisi M. Prostate Cancer Diagnosis and Management Across Twenty Years of Clinical Practice: A Single-center Experience on 2,500 Cases. Anticancer Res. 2019; 39:1397-1401.

4. Pepe P, Aragona F. Morbidity after transperineal prostate biopsy in 3000 patients undergoing 12 vs 18 vs more than 24 needle cores. Urology. 2013; 81:1142-46.

15. Grummet J. How to Biopsy: Transperineal Versus Transrectal, Saturation Versus Targeted, What's the Evidence? Urol Clin North Am. 2017; 44(4):525-534.

5. Tan WP, Papagiannopoulos D, Latchamsetty KC, et al. Predictors of fluoroquinolone-resistant bacteria in the rectal vault of men undergoing prostate biopsy. Prostate Cancer Prostatic Dis. 2019; 22(2):350.

16. Grummet JP, Weerakoon M, Huang S, et al. Sepsis and 'superbugs': should we favour the transperineal over the transrectal approach for prostate biopsy?BJU Int. 2014; 114:384-88.

6. Papagiannopoulos D, Abern M, Wilson N, et al. Predictors of Infectious Complications after Targeted Prophylaxis for Prostate Needle Biopsy. J Urol. 2018; 199(1):155-160.

17. Liss MA, Ehdaie B, Loeb S, et al. An Update of the American Urological Association White Paper on the Prevention and Treatment of the More Common Complications Related to Prostate Biopsy. J Urol. 2017; 198:329-334.

7. Queiroz MRG, Falsarella PM, Mariotti GC, et al. Comparison of complications rates between multiparametric magnetic resonance imaging-transrectal ultrasound (TRUS) fusion and systematic TRUS prostatic biopsies. Abdom Radiol (NY). 2019; 44(2):732-738.

18. Mottet N, van den Bergh RCN, Briers E, et al. Van den Broeck T, Cumberbatch M, Fossati N, Gross T, Lardas M, Liew M, Moris L, Schoots IG, Willemse PPM. EAU 2019 Prostate Cancer GUIDE LINE.

Advances in Urological Diagnosis and Imaging - 2020; 3,1

P. Pepe, A. Fandella.

19. Jiang P, Liss MA, Szabo RJ. Targeted Antimicrobial Prophylaxis Does Not Always Prevent Sepsis after Transrectal Prostate Biopsy. J Urol. 2018; 200:361-368.

26. Elshal AM, Atwa AM, El-Nahas AR, et al. Chemoprophylaxis during transrectal prostate needle biopsy: critical analysis through randomized clinical trial. World J Urol. 2018; 36(11):1845-1852.

20. Cheung C, Patel HD, Landis P, et al. Targeted antimicrobial prophylaxis for transrectal ultrasound-guided prostate biopsy during active surveillance: Effect on hospitalization. Urol Oncol. 2018; 36(4):158.e7-158.e12.

27. Simmons MN, Neeb AD, Johnson-Mitchell M. Reduced Risk of Sepsis after Prostate Biopsy Using a Cephalosporin-Fluoroquinolone Antibiotic Regimen and Isopropyl Alcohol Needle Washing. Urology. 2018; 115:102-106.

21. Pilatz A, LuĚ&#x2C6;decke G, Wagenlehner F. Prophylaxis of infectious complications following prostate biopsy. Urologe A. 2017; 56(6):759-763.

28. Boehm K, Siegel FP, Schneidewind L, et al. Antibiotic Prophylaxis in Prostate Biopsies: Contemporary Practice Patterns in Germany. Front Surg. 2018; 5:2.

22. Hiyama Y, Takahashi S, Uehara T, et al. Selective culture of Escherichia coli to prevent infective complications of transrectal ultrasound-guided prostate biopsy: Clinical efficacy and analysis of characteristics of quinolone-resistant Escherichia coli. Int J Urol. 2019. 23. Van Besien J, Uvin P, Weyne E, et al. Use of fosfomycin as targeted antibiotic prophylaxis before prostate biopsy: A prospective randomized study. Int J Urol. 2019; 26:391-397.

29. Cheung C, Patel HD, Landis P, et al. Targeted antimicrobial prophylaxis for transrectal ultrasound-guided prostate biopsy during active surveillance: Effect on hospitalization. Urol Oncol. 2018; 36(4):158.e7-158.e12. 30. Pepdjonovic L, Tan GH, Huang S, et al. Zero hospital admissions for infection after 577 transperineal prostate biopsies using singledose cephazolin prophylaxis.World J Urol. 2017; 35(8):1199-1203.

24. Roberts MJ, Scott S, Harris PN, et al. Comparison of fosfomycin against fluoroquinolones for transrectal prostate biopsy prophylaxis: an individual patient-data meta-analysis. World J Urol. 2018; 36: 323-330.

31. Toner L, Bolton DM, Lawrentschuk N. Prevention of sepsis prior to prostate biopsy. Investig Clin Urol. 2016; 57(2):94-9.

25. Carignan A, Sabbagh R, Masse V, et al. Effectiveness of fosfomycin tromethamine prophylaxis in preventing infection following transrectal ultrasound-guided prostate needle biopsy: Results from a large Canadian cohort. J Glob Antimicrob Resist. 2019; 17:112-116.

33. Fandella A, Scattoni V, Galosi A, et al. Italian Prostate Biopsies Group: 2016 Updated Guidelines Insights. Anticancer Res. 2017; 37(2):413-424.

32. Miller J, Perumalla C, Heap G. Complications of transrectal versus transperineal prostate biopsy. ANZ J Surg. 2005; 75:48-50.

CORRESPONDENCE Pietro Pepe, MD Urology Unit - Cannizzaro Hospital, Via Messina 829, Catania (Italy) E-mail: piepepe@hotmail.com Phone. + 39 95 7263285 Fax. + 39 95 7263259

Advances in Urological Diagnosis and Imaging - 2020; 3,1

KEY TOPICS

Focus on management of negative fusion biopsy on PI-RADS 4-5 prostatic lesions

Pasquale Martino 1, Michele Barbera 2. 1 2

Dipartimento d’Emergenza e dei Trapianti d’Organo, Urologia, Andrologia e Trapianti di Reni, Università di Bari, Italy; U.O. Urologia – Presidio Ospedaliero di Sciacca – ASP Agrigento, Italy.

Technological advancement and the routine employment of mpMRI allow a more precise execution of prostate biopsies. However, there are limits to overcome in regards to Pirads 4 and 5 with negative histology. This gap is fundamentally due to Imaging readers’ inexperience, and this limit may be further strengthened by a bioptic execution performed by a urologist who is not skilled on imaging and/or with an execution of biopsies with a low number of core target.

SUMMARY

KEY WORDS: Fusion biopsy, mpMRI, PI-RIDAS 4-5. Currently, in the field of imaging, the best methodology to locate prostatic neoplastic lesions and to delineate the anatomy of the prostate and of the surrounding tissues is the multiparametric MRI of the prostate. Furthermore, the same method is extremely useful to select patients for in Active Surveillance (4). Recent European guidelines (ESUR March 2019) recommend the study of multiparametric MRIof the prostate (mpMRI) BEFORE the prostatic biopsy due to the fundamental predictive value of this methodology, namely: if the mpMRI is negative (PIRADS 1-2), it is highly probable (9098%) (7) that the patient does not have a prostate tumor which is clinically significant. However, sometimes, rather than making the procedure faster, the RM causes dilemmas to arise. As a matter of fact, at times the biopsy of lesions labeled Pirads 4 (33%) or 5 (18%) can also result as negative (2, 8). At this point it is worth asking if the lesions highlighted by the mpMRI might be false positives (FP). In the transition zone (TZ), the FP rate of the inexperienced radiologists 59% (17/29) was significantly higher (χ2P=0.033) than that of the experienced radiologist 33% (13/40, especially when such lesions are located in this area in which, due to the growth of the adenoma, the area becomes more vascularized and delineated by not well-defined outlines.

All of this makes the “radiological misreading” more likely to happen. Thus, what to do when facing these cases? Should we turn to literature? There are few scientific works, and almost none of them is worthy of consideration. The originof negative biopsies of Pirads 4 and 5 (1, 2) is not easy to highlight. The error might lie at the start in the moment of the execution of the exam and in its interpretation, or within the technique of the execution of the biopsy (both operator-dependent steps). Many works belonging to the specific literature suggest the employment of equipment whichis rarely accessible to all (3T machines and/or with endorectal or 32-channel surface coils). In clinical practice, on local territory, the supply usually consists of 1,5T machines, with 8 or 12-channel surface coils. Furthermore, it is likely that the execution of the exam might be run by radiologists who are not experienced in performing this technique. To sum up, we believe that the resonance exam is not a test that can be assigned to any radiologist, rather, it is more advisable to assign it to a dedicated radiologist, who needs to be an expert in resonance and with whom there is an established learning curve and exchange of clinical and pathological information. To reduce the rate of MR false positives (FP) (3, 5), one of the options is to review the baseline mpMRI and eventually to repeat mpMRI in high volume center if the expert radiologist suggested a repeated imaging. Furthermore, it is to be taken into consideration that currently, with version 2 of PIRAS, many score 3 may be labeled as 4, thereby attributing a significant weight on the reader’s experience (variability inter and intra operator). It should also be noted that PIRADS 5 (which, ultimately, are large-sized PIRADS 4) might be caused by inflammation in extra-low percentages. (clinical evaluation, PSADensity, case history for prostatic neoplasia thus become fundamental).Therefore we suggest to review the pathologist report or slides to rule out inflammation. Advances in Urological Diagnosis and Imaging - 2020; 3,1

P. Martino, M, Barbera.

As far as the biopsy technique (which is usually assigned to a urologist) is concerned, it can be affirmed that to reduce the margin of FP, it is necessary to carry out further sampling of Pirads 4 and 5 zones by employing targeting. The goal therefore becomes to establish the amount of cores to perform on the target lesion. Many authors limit themselves to 2 or 3, however probably more cores are needed in order to reduce the diagnostic margin of error. In conclusion, the review of mpMRI becomes recommended. It is fundamental to standardize the evaluation criteria of the mp MRI. The employment of more readers on mpMRI of negative biopsies may reduce FP. For Pirads 4 or 5 lesions (3) with initial negative biopsy, the evidence is too weak to recommende a re-biopsy within a very short period of time, preferably a core target plus random. Regarding the type of biopsy to employ to approach the lesion, the literature does not report significant differences on transrectal (TR) or transperineal (TP) executions. Thus, a TR or TP approach is to be chosen depending on where the lesion is located. Anterior lesions cannot undergo a precise TP biopsy due to a «shield» effect of the pubic symphysis, and conversely, due to large-sized prostates, a transrectal route of the apex can be difficult to perform using biplanar probes (6). Ultimately, it can be affirmed that particularly in relationship with a follow-up biopsy (systemic and target), it is necessary to standardize and stress as much as possible the mpMRI methodologies to ensure that the biopsy will not be performed in vain.

REFERENCES 1.TinekeT. Stolk, IgleJan de Jong,Thomas C. Kwee1, et al. False positives in PIRADS (V2) 3, 4, and 5 lesions: relationship with reader experience and zonal location.AbdominalRadiology. 2019; 44:1044-51. 2. Sheridan AD, Nath SK, Aneja S, et al. MRI-ultrasoundfusiontargetedbiopsy of prostate imaging reporting and data systemversion 2 category 5 lesionsfound false-positive atmultiparametric prostate MRI. Am. J.Roentgenol. 2018; 210:W218-W225. 3. Hambrock T, Somford DM, Hoeks C, et al. MagneticResonanceImagingGuided Prostate BiopsyinMen With Repeat Negative Biopsies and Increased Prostate SpecificAntigen.J. Urol. 2010; 183(2): 520-8. 4. Hassan O, Han M, Zhou A, et al.Incidence of Extraprostatic Extension at Radical Prostatectomy with PureGleason Score 3 + 3 = 6 (Grade Group 1) Cancer: Implicationsfor WhetherGleason Score 6 Prostate CancerShould be Renamed“NotCancer” and for SelectionCriteria for Active Surveillance, J. Urol. 2018; 199(6):1482-1487. 5. Hauth E, Jaeger H, Hohmuth H, et al. Follow-up MR imaging of PIRADS 3 and PI-RADS 4 prostate lesions.ClinImaging. 2017; 43:64-68. 6. GalosiAB, Tiroli M, Cantoro D, et al Biopsy of the anterior prostate gland: technique with end-fire transrectal ultrasound. Archivio Ital Urol. 2018; 82(4):248-52. 7. Liang Z, Xiaoqiang L, Chen Y, et al. Accuracy of multiparametric magnetic resonance imaging for diagnosing prostate Cancer: a systematic review and meta-analysis. BMC Cancer. 2019; 19:12-44. 8. Rourke E, Sunnapwar A, Mais D, et al. Inflammation appears as high Prostate Imaging–Reporting and Data System scores on prostate magnetic resonance imaging (MRI) leading to false positive MRI fusion biopsy. InvestigClin Urol. 2019; 60(5):388-395.

CORRESPONDENCE Prof. a.c. Pasquale Martino Università di Bari E-mail: pasqualeluciomartino@libero.it

Advances in Urological Diagnosis and Imaging - 2020; 3,1

RAPID

COMMUNICATION

An innovative tool that will make the wearing of face masks more comfortable Camilla Capretti 1, Margherita Bora 2, Romina Pesaresi 2, Raffaela Marangi 2, Mariaconcetta Cortini 2, Lorella Scarciglia 2, Sandra Silvestri 2, Andrea Galosi 1. 1 2

Institute of Urology, Marche Polytechnic University, School of Medicine, “Ospedali Riuniti”, 60126, Ancona, Italy; Operating Room Nursing Staff, “Ospedali Riuniti”, 60126, Ancona, Italy.

A technician, specialised in construction equipment, found a way to help medical staff on the front line of the coronavirus outbreak. He used his 3D printer to make a hundred of ‘’ear guards’’ and donated these tools to the local hospital. An ‘’ear guard’’ is so simple, but it is incredibly effective to alleviate the pressure of wearing a face mask all day.

SUMMARY

KEY WORDS: COVID-19; surgical mask; personal protection equipment; ear guard.

In light of the coronavirus pandemic ravaging the world, masks are crucial to prevent the spread of COVID-19, particularly amongst medical personnel (1). Doctors, nurses and all health workers have to wear face masks from the beginning to the end of their shifts, but the masks provided are not particularly comfortable, because they put pressure on the head and cause friction against the ears (Figure 1). G. C., a 39-year-old technician from Ancona, specialised in construction equipment, responded to the call for help by

the nurses of our Hospital and figured out a brilliant way to relieve the pain of medical workers, who wear protective gear all day long, every single day, on the frontlines. C. used his 3D printer to make a plastic “ear guard” that prevents the elastic bands of the mask from rubbing against the back of the nurse/surgeon’s ears. He donated a hundred of these tools to hospital workers. He found the prototypes online (the template is available to download from the open-source 3D printing community “Thingiverse”) and used common plastic material to create these items (Figure 2). This material is washable, reusable and relatively cheap. The device is very easy to wear, it goes behind the head and can be used with or without surgical cap. Thanks to its notches, the wearer can loop the elastic bands of the mask around whichever notche he finds most comfortable, on either side of the guard; this will adjust the tension on the head while keeping the mask firmly in place (Figure 3). In this difficult moment, characterized by increasing costs versus persistent spending cuts (2), these generous gestures and intelligent ideas are needful for the healthcare system and can make a difference in the medical personnel’s routine (Table 1).

Figure 1. The mask causes friction against the backs of the ears and slips under the nose.

Advances in Urological Diagnosis and Imaging - 2020; 3,1

C. Capretti, M. Bora, R. Pesaresi, R. Marangi, M. Cortini, L. Scarciglia, S. Silvestri, A. Galosi. Figure 2. C.’s 3D printer is printing the devices.

Figure 3. The “ear guard” transfers the tension of the mask straps from the ears to the special 3D printed strap on the back of a nurse’s head.

Table 1. Advantage of the “ear guard” to hold the surgical mask 1. Prevent dislodgement of the mask under the nose. It happens in talking 2. Avoid tension of the elastic bands of the mask on the upper margin of the ear and their scratching on the ear skin 3. Can be worn over the surgical cap, instead under 4. Reusable and easy to wash 5. Suitable for any head size, even with the hair collected under the cap

REFERENCES 1. Qing-Xia Ma, Hu Shan et al. Potential utilities of mask-wearing and instant hand hygiene for fighting SARS-COv2 J Med Virol. 2020 Mar 3. 2. Lucchese M, Pianta M. The Coming Coronavirus Crisis: What Can We Learn? Inter Econ. 2020; 55(2):98-104. No direct or indirect commercial financial incentive associated with the publishing of this article, and no recognized financial or commercial interests.

CORRESPONDENCE Camilla Capretti Institute of Urology, “Ospedali Riuniti”, via Conca, 71 - 60126, Ancona, Italy. e-mail: camilla.capretti2@gmail.com Phone: +39 3899978783

Advances in Urological Diagnosis and Imaging - 2020; 3,1

Istruzioni Autori AUDI.qxp_Stesura Seveso 29/11/18 10:15 Pagina 1

Instructions to Authors AIMS AND SCOPE

REFERENCES

Advances in Urological Diagnosis and Imaging is a free open access journal. The Journal has the purpose of promote, spread and favorite the scientific knowledge and research in diagnosis and imaging in Urology, Andrology and Nephrology. Advances in Urological Diagnosis and Imaging publishes every 4 months original articles, reviews, case reports, position papers, guidelines, editorials, abstracts and congress proceedings.

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